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CAS No. : | 77-09-8 | MDL No. : | MFCD00005913 |
Formula : | C20H14O4 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | KJFMBFZCATUALV-UHFFFAOYSA-N |
M.W : | 318.32 | Pubchem ID : | 4764 |
Synonyms : |
Phthalimetten
|
Chemical Name : | 3,3-Bis(4-hydroxyphenyl)isobenzofuran-1(3H)-one |
Num. heavy atoms : | 24 |
Num. arom. heavy atoms : | 18 |
Fraction Csp3 : | 0.05 |
Num. rotatable bonds : | 2 |
Num. H-bond acceptors : | 4.0 |
Num. H-bond donors : | 2.0 |
Molar Refractivity : | 88.67 |
TPSA : | 66.76 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | Yes |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | Yes |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.53 cm/s |
Log Po/w (iLOGP) : | 2.13 |
Log Po/w (XLOGP3) : | 2.41 |
Log Po/w (WLOGP) : | 3.45 |
Log Po/w (MLOGP) : | 3.05 |
Log Po/w (SILICOS-IT) : | 3.85 |
Consensus Log Po/w : | 2.98 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -3.75 |
Solubility : | 0.056 mg/ml ; 0.000176 mol/l |
Class : | Soluble |
Log S (Ali) : | -3.45 |
Solubility : | 0.112 mg/ml ; 0.000352 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -6.43 |
Solubility : | 0.000118 mg/ml ; 0.000000372 mol/l |
Class : | Poorly soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 0.0 |
Synthetic accessibility : | 2.86 |
Signal Word: | Danger | Class: | 9 |
Precautionary Statements: | P201-P202-P280-P308+P313-P405-P501 | UN#: | 3077 |
Hazard Statements: | H340-H350-H361 | Packing Group: | Ⅲ |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | at 80℃; for 0.0833333 h; | 500 mg of phthalic anhydride, 500 mg of phenol and 1 g of crude catalyst derived from Thlaspi (Example 1.1, 12N HCl) dehydrated at 110° C. for a few minutes are placed in a single-necked flask and heated at 80° C. for 5 minutes. (0510) After cooling down, the reaction mixture is diluted in 5 mL of a water/ethanol mixture. 1 mL of solution is taken then added to a 3M soda solution. (0511) In the case of phenolphthalein, the solution becomes pink immediately. (0512) After washing with ether, the phenolphthalein crystallizes easily. |
89% | at 120℃; for 24 h; Inert atmosphere | Preparation of Phenolphthalein Using Zinc-Containing Ionic Liquid Catalyst Compositions.; In a 250 mL round bottom flask equipped with mechanical stirrer, thermometer, nitrogen inlet and reflux condenser, 10.0 g of phthalic anhydride (0.067 moles) and 15 g of ionic liquid catalyst composition (zinc chloride and 1-butyl-3-methyl-imidazolium) (60 wt. percent based on total weight of reactants) were charged to the round bottom flask followed by 14.3 g phenol (2.25 molar equivalents based on phthalic anhydride) and 1.9 g chlorosulphonic acid (0.2 molar equivalents based on phthalic anhydride), while maintaining the round bottom flask in a nitrogen atmosphere at 50 to 60° C. The reaction mixture was then heated with stirring at 120° C. (bath temperature). Over the course of the reaction (24 hours), the reaction mass progressively turned from orange to brownish orange to deep brown. After 24 hours, the reaction mixture comprising phenolphthalein was then quenched with 150 mL toluene. The viscous mass produced by the addition of toluene was stirred at 85° C. for about 30 min. The supernatant (containing the ionic liquid catalyst composition, toluene, and unreacted starting material) was decanted and the remaining viscous mass was then heated with 150 mL water and stirred at 85° C. for about 30 min. The solidified phenolphthalein was filtered while hot and washed until the supernatant was neutral with cold, distilled water to obtain crude phenolphthalein. The resulting brownish yellow solid was dried under vacuum at 100° C. overnight. The yield of crude phenolphthalein was 18.7 g (89 mol percent) and the purity was 96.08 wt. percent. |
88% | at 140℃; for 48 h; Inert atmosphere | Example 1; Preparation of Phenolphthalein: A Procedure for the Preparation of phenolphthalein using metal oxide catalysts is as follows. In a 250 mL, round bottom flask equipped with mechanical stirrer, thermometer, nitrogen inlet, and reflux condenser, 18.5 g of phthalic anhydride and 27.6 g of phenol were charged, followed by 10.0 g of heterogeneous catalyst (tungstated zirconia) and 1.9 g of chlorosulphonic acid ("CSA"), while maintaining the round bottom flask in a nitrogen atmosphere at 50 to 60° C. This amounted to 2.25 molar equivalents of phenol with respect to the phthalic anhydride, and 17percent by weight loading of the catalyst.The reaction mixture was then heated with stirring at 140° C. (bath temperature). During the course of the reaction for 48 hours, the reaction mass progressively turned from orange to brownish orange to deep brown. The reaction product was then quenched (stopped) with a solvent (160 mL of methanol). The quenched mass comprising phenolphthalein (PP), unreacted phthalic anhydride (PA), and by-products was stirred at 85° C. for about 30 minutes. All organic compounds including the phenolphthalein dissolved in the methanol. The solution was then filtered to remove the solid catalyst as a residue and obtain a filtrate. The methanol was removed from the filtrate using a Rotovac.(R). evaporator, and the viscous mass was then heated with 160 mL of toluene solvent and stirred at 85° C. for 30 minutes. The toluene removed unreacted reactants and by-products. The solid, crude precipitate, which did not dissolve in the toluene, was filtered while hot and washed with hot water. The resulting brownish yellow solid was dried under vacuum at 100° C. overnight to obtain crude phenolphthalein. The isolated yield of crude phenolphthalein was 35.0 g (88 wt. percent, based on the phthalic anhydride), and the purity was 95.9percent, as determined by HPLC as described above.Phenolphthalein was prepared under the same conditions, except for using tungstated ceria and molybdenum on silica. The results of the various methods of preparing phenolphthalein are shown in Table 1 below, using the same analytical procedures as in Example 1. In Table 1, the "conversion" and "reaction yield" were determined just before quenching with methanol as described above. The "isolated yield" and "purity" in Table 1 refers to the crude phenolphthalein (after filtering and washing) according to the method described above. |
84.2% | at 50 - 115℃; for 17 - 20 h; | Comparative Example A; In a 250 milliliter (mL) round bottom flask equipped with mechanical stirrer, thermometer, nitrogen inlet and reflux condenser, 18.5 gram (g) (0.124 mole) of phthalic anhydride and 9.99 g (0.073 mole) of zinc chloride were charged followed by 26.25 g (0.278 mole) phenol and 2.91 g (0.024 mole) chloro sulphonic acid, while maintaining the round bottom flask in nitrogen atmosphere at 50 to 60° C. The reaction mixture was then heated with stirring at 115° C. During the course of the reaction of 18 to 20 hours, the reaction mixture progressively turned from yellowish orange to brownish orange to deep brown while gaining viscosity. The reaction mixture was then treated with 250 mL hot water (50 to 90° C.). The treated mixture was stirred further for about 30 minutes at 80 to 85° C. The treated mixture was filtered while hot and washed with cold de-ionized water, then dried in an oven, resulting in a crude phenolphthalein material. The crude phenolphthalein material comprises 95 wt percent phenolphthalein based on the total weight of the material. The molar yield based on phthalic anhydride was 90percent.; Example 1; In a 250 mL round bottom flask equipped with mechanical stirrer, thermometer, nitrogen inlet and reflux condenser, 18.5 g (0.124 mole) of phthalic anhydride and 9.99 g (0.073 mole) of zinc chloride were charged followed by 26.25 g (0.278 mole) phenol and 2.91 g (0.024 mole) chlorosulphonic acid, while maintaining the round bottom flask in nitrogen atmosphere at 50 to 60° C. The reaction mixture was then heated with stirring at 115° C. for 18 to 20 hours. During the course of the reaction of 18 to 20 hours, the reaction mass progressively turned from yellowish orange to brownish orange to deep brown while gaining viscosity. The reaction mass was cooled to room temperature and a solvent system containing a mixture of methanol and toluene (10:90, v:v) was added and stirred for 1 hour at reflux. The viscous mass became very free and the product was filtered. Hot water (50 to 90° C.) was added and then the reaction mixture was heated at 80 to 85° C. for 30 minutes and then cooled to room temperature. The resulting brownish yellow solid was dried in an oven at 100° C., over night. The solid comprised 98 wt percent phenolphthalein based on the total weight of the solid as analyzed by HPLC. The molar yield based on phthalic anhydride was 85percent.; Comparative Example B; In a 500 mL four neck round bottom flask fitted with an overhead stirrer, a nitrogen gas inlet, thermowell, and a reflux condenser were placed 100.0 g (0.675 mole) of phthalic anhydride, 143.0 g (1.52 mole) of phenol, 55.20 g of zinc chloride (0.40 mole), and 15.73 g of chloro sulphonic acid (0.135 mole). A slow stream of nitrogen gas was continuously passed through the flask, and the reaction mixture was heated at 115° C. for 17 to 18 hours. The reaction mixture was allowed to cool to 50° C. then 900 mL of water was added to the reaction mixture followed by stirring for 2 hours at 85 to 90° C. The slurry formed was filtered out, washed with 100 mL water for 5 times until free from acid, and dried, resulting in crude phenolphthalein material. The yield of this process was 190.50 g (89 mol percent) based on the moles of phthalic anhydride. The crude phenolphthalein material comprised less than or equal to 95 wt percent phenolphthalein based on the total weight of the material.; Examples 21-23; 18.5 g (0.124 mole) of phthalic anhydride, 9.99 g (0.073 mole) of zinc chloride, 26.25 g (0.278 mole) phenol and 2.91 g (0.024 mole) chlorosulphonic acid were reacted under nitrogen at 110° C. for 18 hours. The reaction mass was cooled to 50 to 60° C. and a solvent system containing a mixture of methanol and toluene (10:90, v:v) was added in the amounts shown in Table 2. The resulting mixture is stirred at reflux temperature for 2 hours, and then cooled to 0 to 10° C. and maintained at 0 to 10° C. for 0.5 to 1.0 hour. In some examples the reaction mass was treated with the solvent system more than once as shown in Table 2. After filtering, the solid was washed with 300 mL of hot water (50 to 90° C., or more specifically, 70° C.), filtered and dried. Yields and purities are shown in Table 2. Yield is in mole percent based on the amount of phthalic anhydride. Purity is in wt percent based on the total weight of the solid material. These examples show that using a solvent system comprising a polar organic solvent is an efficient method to obtain high purity phenolphthalein in a simple and efficient manner. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With mixed metal catalyst derived from Thlaspi; at 80℃; for 0.0833333h; | 500 mg of phthalic anhydride, 500 mg of phenol and 1 g of crude catalyst derived from Thlaspi (Example 1.1, 12N HCl) dehydrated at 110 C. for a few minutes are placed in a single-necked flask and heated at 80 C. for 5 minutes. (0510) After cooling down, the reaction mixture is diluted in 5 mL of a water/ethanol mixture. 1 mL of solution is taken then added to a 3M soda solution. (0511) In the case of phenolphthalein, the solution becomes pink immediately. (0512) After washing with ether, the phenolphthalein crystallizes easily. |
89.00% | chlorosulfonic acid; at 120℃; for 24h;Inert atmosphere;Product distribution / selectivity; | Preparation of Phenolphthalein Using Zinc-Containing Ionic Liquid Catalyst Compositions.; In a 250 mL round bottom flask equipped with mechanical stirrer, thermometer, nitrogen inlet and reflux condenser, 10.0 g of phthalic anhydride (0.067 moles) and 15 g of ionic liquid catalyst composition (zinc chloride and 1-butyl-3-methyl-imidazolium) (60 wt. % based on total weight of reactants) were charged to the round bottom flask followed by 14.3 g phenol (2.25 molar equivalents based on phthalic anhydride) and 1.9 g chlorosulphonic acid (0.2 molar equivalents based on phthalic anhydride), while maintaining the round bottom flask in a nitrogen atmosphere at 50 to 60 C. The reaction mixture was then heated with stirring at 120 C. (bath temperature). Over the course of the reaction (24 hours), the reaction mass progressively turned from orange to brownish orange to deep brown. After 24 hours, the reaction mixture comprising phenolphthalein was then quenched with 150 mL toluene. The viscous mass produced by the addition of toluene was stirred at 85 C. for about 30 min. The supernatant (containing the ionic liquid catalyst composition, toluene, and unreacted starting material) was decanted and the remaining viscous mass was then heated with 150 mL water and stirred at 85 C. for about 30 min. The solidified phenolphthalein was filtered while hot and washed until the supernatant was neutral with cold, distilled water to obtain crude phenolphthalein. The resulting brownish yellow solid was dried under vacuum at 100 C. overnight. The yield of crude phenolphthalein was 18.7 g (89 mol %) and the purity was 96.08 wt. %. |
88% | With chlorosulfonic acid;15 wt.% tungsten oxide on zirconia; at 140℃; for 48h;Inert atmosphere;Product distribution / selectivity; | Example 1; Preparation of Phenolphthalein: A Procedure for the Preparation of phenolphthalein using metal oxide catalysts is as follows. In a 250 mL, round bottom flask equipped with mechanical stirrer, thermometer, nitrogen inlet, and reflux condenser, 18.5 g of phthalic anhydride and 27.6 g of phenol were charged, followed by 10.0 g of heterogeneous catalyst (tungstated zirconia) and 1.9 g of chlorosulphonic acid (?CSA?), while maintaining the round bottom flask in a nitrogen atmosphere at 50 to 60 C. This amounted to 2.25 molar equivalents of phenol with respect to the phthalic anhydride, and 17% by weight loading of the catalyst.The reaction mixture was then heated with stirring at 140 C. (bath temperature). During the course of the reaction for 48 hours, the reaction mass progressively turned from orange to brownish orange to deep brown. The reaction product was then quenched (stopped) with a solvent (160 mL of methanol). The quenched mass comprising phenolphthalein (PP), unreacted phthalic anhydride (PA), and by-products was stirred at 85 C. for about 30 minutes. All organic compounds including the phenolphthalein dissolved in the methanol. The solution was then filtered to remove the solid catalyst as a residue and obtain a filtrate. The methanol was removed from the filtrate using a Rotovac evaporator, and the viscous mass was then heated with 160 mL of toluene solvent and stirred at 85 C. for 30 minutes. The toluene removed unreacted reactants and by-products. The solid, crude precipitate, which did not dissolve in the toluene, was filtered while hot and washed with hot water. The resulting brownish yellow solid was dried under vacuum at 100 C. overnight to obtain crude phenolphthalein. The isolated yield of crude phenolphthalein was 35.0 g (88 wt. %, based on the phthalic anhydride), and the purity was 95.9%, as determined by HPLC as described above.Phenolphthalein was prepared under the same conditions, except for using tungstated ceria and molybdenum on silica. The results of the various methods of preparing phenolphthalein are shown in Table 1 below, using the same analytical procedures as in Example 1. In Table 1, the ?conversion? and ?reaction yield? were determined just before quenching with methanol as described above. The ?isolated yield? and ?purity? in Table 1 refers to the crude phenolphthalein (after filtering and washing) according to the method described above. |
84.2 - 90% | chlorosulfonic acid; zinc(II) chloride; at 50 - 115℃; for 17 - 20h;Product distribution / selectivity; | Comparative Example A; In a 250 milliliter (mL) round bottom flask equipped with mechanical stirrer, thermometer, nitrogen inlet and reflux condenser, 18.5 gram (g) (0.124 mole) of phthalic anhydride and 9.99 g (0.073 mole) of zinc chloride were charged followed by 26.25 g (0.278 mole) phenol and 2.91 g (0.024 mole) chloro sulphonic acid, while maintaining the round bottom flask in nitrogen atmosphere at 50 to 60 C. The reaction mixture was then heated with stirring at 115 C. During the course of the reaction of 18 to 20 hours, the reaction mixture progressively turned from yellowish orange to brownish orange to deep brown while gaining viscosity. The reaction mixture was then treated with 250 mL hot water (50 to 90 C.). The treated mixture was stirred further for about 30 minutes at 80 to 85 C. The treated mixture was filtered while hot and washed with cold de-ionized water, then dried in an oven, resulting in a crude phenolphthalein material. The crude phenolphthalein material comprises 95 wt % phenolphthalein based on the total weight of the material. The molar yield based on phthalic anhydride was 90%.; Example 1; In a 250 mL round bottom flask equipped with mechanical stirrer, thermometer, nitrogen inlet and reflux condenser, 18.5 g (0.124 mole) of phthalic anhydride and 9.99 g (0.073 mole) of zinc chloride were charged followed by 26.25 g (0.278 mole) phenol and 2.91 g (0.024 mole) chlorosulphonic acid, while maintaining the round bottom flask in nitrogen atmosphere at 50 to 60 C. The reaction mixture was then heated with stirring at 115 C. for 18 to 20 hours. During the course of the reaction of 18 to 20 hours, the reaction mass progressively turned from yellowish orange to brownish orange to deep brown while gaining viscosity. The reaction mass was cooled to room temperature and a solvent system containing a mixture of methanol and toluene (10:90, v:v) was added and stirred for 1 hour at reflux. The viscous mass became very free and the product was filtered. Hot water (50 to 90 C.) was added and then the reaction mixture was heated at 80 to 85 C. for 30 minutes and then cooled to room temperature. The resulting brownish yellow solid was dried in an oven at 100 C., over night. The solid comprised 98 wt % phenolphthalein based on the total weight of the solid as analyzed by HPLC. The molar yield based on phthalic anhydride was 85%.; Comparative Example B; In a 500 mL four neck round bottom flask fitted with an overhead stirrer, a nitrogen gas inlet, thermowell, and a reflux condenser were placed 100.0 g (0.675 mole) of phthalic anhydride, 143.0 g (1.52 mole) of phenol, 55.20 g of zinc chloride (0.40 mole), and 15.73 g of chloro sulphonic acid (0.135 mole). A slow stream of nitrogen gas was continuously passed through the flask, and the reaction mixture was heated at 115 C. for 17 to 18 hours. The reaction mixture was allowed to cool to 50 C. then 900 mL of water was added to the reaction mixture followed by stirring for 2 hours at 85 to 90 C. The slurry formed was filtered out, washed with 100 mL water for 5 times until free from acid, and dried, resulting in crude phenolphthalein material. The yield of this process was 190.50 g (89 mol %) based on the moles of phthalic anhydride. The crude phenolphthalein material comprised less than or equal to 95 wt % phenolphthalein based on the total weight of the material.; Examples 21-23; 18.5 g (0.124 mole) of phthalic anhydride, 9.99 g (0.073 mole) of zinc chloride, 26.25 g (0.278 mole) phenol and 2.91 g (0.024 mole) chlorosulphonic acid were reacted under nitrogen at 110 C. for 18 hours. The reaction mass was cooled to 50 to 60 C. and a solvent system containing a mixture of methanol and toluene (10:90, v:v) was added in the amounts shown in Table 2. The resulting mixture is stirred at reflux temperature for 2 hours, and then cooled to 0 to 10 C. and maintained at 0 to 10 C. for 0.5 to 1.0 hour. In some examples the reaction mass was treated with the solvent system more than once as shown in Table 2. After filtering, the solid was washed with 300 mL of hot water (50 to 90 C., or more specifically, 70 C.), filtered and dried. Yields and purities are shown in Table 2. Yield is in mole percent based on the amount of phthalic anhydride. Purity is in wt % based on the total weight of the solid material. These examples show that using a solvent system comprising a polar organic solvent is an efficient method to obtain high purity phenolphthalein in a simple and efficient manner. |
chlorosulfonic acid; at 140℃; for 48h;Inert atmosphere;Product distribution / selectivity; | Example 1 Preparation of Phenolphthalein.; In a 250-ml round bottom flask equipped with mechanical stirrer, thermometer, nitrogen inlet and reflux condenser, 18.5 g of phthalic anhydride and 27.6 g of phenol were charged, followed by 10.0 g of supported heteropolyacid catalyst (silicotungstic acid in Sample 1) and 1.9 g chlorosulphonic acid, while maintaining the round bottom flask in a nitrogen atmosphere at 50 to 60 C. This amounted to 1 molar equivalent of phenolphthalein, 2.25 molar equivalents of phenol with respect to the phthalic anhydride, and 17% by weight loading of the catalyst.The reaction mixture was then heated with stirring at 140 C. (bath temperature). During the course of the reaction for 48 hours, the reaction mass progressively turned from orange to brownish orange to deep brown. The reaction product was then quenched with a solvent, 160 mL of methanol. The quenched mass comprising phenolphthalein, unreacted phthalic anhydride, and by-products was stirred at 85 C. for about 30 min. The solution was then filtered to remove solid catalyst as a residue and to obtain a filtrate containing the phenolphthalein. The methanol was removed from the filtrate using a Rotovac evaporator, and the viscous mass was then heated with 160 mL of toluene, and stirred at 85 C. for 30 min. The precipitated solid (precipitated phenolphthalein) was filtered while hot and washed with hot water. The resulting brownish yellow solid was dried under vacuum at 100 C. overnight to obtain crude phenolphthalein. The yield of crude phenolphthalein was 35.0 g (88% by weight of the crude phenolphthalein). The purity was 95.88%, as determined by HPLC.Phenolphthalein was also prepared using the above procedure and 15 wt. tungstophosphoric acid/zirconia, 15 wt. % tungstophosphoric acid/titania, and 15 wt. % wt. % tungstophosphoric acid/22.4 wt. % ZrO2 on 62.6 wt. % SBA-15 zeolite. The results are shown in Table 1. | |
With hydrogenchloride; In ethanol; water; | - phenolphthalein 500 mg of phthalic anhydride, 500 mg of phenol and 1 g of crude catalyst derived from Thlaspi (Example 1.1, 12N HCl) dehydrated at 110C for a few minutes are placed in a single-necked flask and heated at 80C for 5 minutes. After cooling down, the reaction mixture is diluted in 5 mL of a water/ethanol mixture. 1 mL of solution is taken then added to a 3M soda solution. In the case of phenolphthalein, the solution becomes pink immediately. After washing with ether, the phenolphthalein crystallizes easily. | |
With hydrogenchloride; In water; at 80℃; for 0.0833333h; | 500mg of phthalic anhydride, 500mg of phenol and1 g of crude catalyst derived from Thiaspi (ReferenceExample 1.1, 12N HC1) dehydrated at 1100 C. for a fewminutes are placed in a single-necked flask and heated at 80C. for 5 minutes.After cooling down, the reaction mixture is dilutedinS mL of a water/ethanol mixture. 1 mL of solution is takenthen added to a 3M soda solution.In the case ofphenolphthalein, the solution becomes pink immediately.After washing with ether, the phenolphthalein crystallizes easily. | |
With chlorosulfonic acid; zinc(II) chloride; | A process for production of PPPBP is optionally a two-step process, where the first step is making PP in a batch reactor with a cycle time of 15-20 hours (hrs). Phthalic anhydride is reacted with phenol in the presence of ZnCl2 as a catalyst and chloro sulfonic acid (CSA) as a co-catalyst. The purification and isolation of phenolphthalein is also performed batch-wise where the phenolphthalein reaction mass is cooled to 65C and partially dissolved in methanol-water mixture to make the reaction mass flow. The reaction mass is then transferred to another vessel and completely dissolved in a 90% methanol in water, and further treated with activated charcoal and sodium bisulfite. The slurry reaction mass is then filtered to remove the charcoal and collected in a separate vessel. The reaction mass is then boiled away to evaporate more than 50% of the solvent and then cooled to induce to precipitation of the phenolphthalein. The slurry is then separated for solid isolation using multiple centrifuge batches. The product is washed in a centrifuge with hot water and dried in batches. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With sulfuric acid; cis-(2-(1H-imidazol-2-yl)pyridine)-(2-(imidazol-2-yl)pyridine)dioxidovanadate(V) tris(aqua); dihydrogen peroxide; potassium bromide; In methanol; water; at 20℃; for 0.5h;pH 2 - 3; | General procedure: Compound 1 (10.0 mg, 0.0125 mmol) and phenol/aniline-like compound (1.00 mmol)were dissolved in CH3OH:H2O (3:1, 4.0 mL). To this mixture, KBr (360 mg, 3.05 mmol) wasadded, followed by 30% H2O2 (2.0 mL), added dropwise with constant stirring. The pH ofthe solution was adjusted to 2-3 by dropwise addition of 50% H2SO4 solution. The reactionmixture was stirred for 0.5-2 h at room temperature. After the reaction was complete,by monitoring TLC, the reaction mixture was concentrated. Ethyl acetate was usedto extract the residual product. The results of the conversions are listed in Table 2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With palladium 10% on activated carbon; W(OTf)6; hydrogen; acetic acid; at 50℃; under 760.051 Torr; for 12h; | Specific methods are as follows: propiolactone was added (0.36g, 5mmol), palladium on carbon (10%, 26.5mg, 0.025mmol, 0.5mol%) in the reactor and W (OTf)6(107.8mg, 0.1mmol, 2mol%). A hydrogen balloon connected to the top of the reactor, and the reactor was purged with hydrogen gas atmosphere. Hydrogen atmosphere at normal pressure, the reaction was stirred at 135 deg.] C after 12h, detected by gas, gamma- valerolactone complete conversion of starting material, and only n-valeric acid. The method carried out as follows completion of the hydrogenation reaction of the ring-opening reaction system separation, to obtain the desired product n-valeric acid: The reaction was completed reaction mixture was dissolved with methylene chloride, filtered to remove the palladium on carbon catalyst and W (OTf)699% yield measured propionic acid, purity of the product was 99%. NMR data for the product using the embodiment of the present invention is the NMR identified the product as follows:The specific reaction procedure and operation method were the same as in Example 27 except that the substrate used was 2 mmol and lmL of acetic acid was added as a solvent at a reaction temperature of 50 C in 94% yield and 99% purity. The product was subjected to nuclear magnetic identification using the manner described in the present invention, and the NMR data of the product were as follows |
26.3 mg | First, 20.0 grams (g) (0.06283 moles) <strong>[77-09-8]phenolphthalein</strong> (lib), 28.42 g (0.71060 moles) solid NaOH, and 200 milliliters (mL) of distilled water were charged into a round bottom flask, fitted with an overhead stirrer and stirred for 30 minutes. To the dark purple color solution formed, zinc dust (22.9 g, 0.3380 moles) was added. The reaction mixture was stirred at room temperature for 1 hour (hr), then heated to 60C and maintained at this temperature until a gray suspension (due to unreacted Zn dust) formed. The suspension was filtered while hot and washed with water (about 20 mL). The filtrate was acidified with 33% aqueous hydrochloric acid (65 g, 1.780 moles) to pH 3. The resulting off-white precipitate was filtered and washed with 50 mL water. The off-white solid was dried in vacuum to yield 26.3 g (HPLC purity about 95% and LC purity 97%) of dihydro<strong>[77-09-8]phenolphthalein</strong> (Illb) as an off-white solid. [0052] The product was confirmed by LC-Ms, found M/Z: 320.0; M+l peak: 321.34, Molecular weight (Mol. wt): 320.34 grams/mole. IR spectroscopy: FTIR (cm"1): 1658 (C=0), 1497 (quaternary carbon), 1600 (aromatic), 1547-1610 and 1386-1441 (COOH/COO ), 3353 (Ar- OH). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | Phenolphthalein (7 g, 22 mmol) was dissolved in aqueous potassium hydroxide solution (7 g in 70 mL) giving a vivid purple solution. Hydroxylamine hydrochloride (1.71 g, 24 mmol) was added and the solution heated to 8O0C. The reaction was monitored by acidifying a sample of the mixture with acetic acid, filtering off the precipitate and adding potassium hydroxide. When no pink colour was observed on the addition of potassium hydroxide the reaction was left stirring for another 5 min. Ethanol (14 mL) was added, and acetic acid was added dropwise until the solution was slightly acidic. A sulphur yellow precipitate formed and was washed with water and dissolved in hot sulphuric acid (10%, 140 mL) giving a bright yellow solution that was refluxed for 2 h. On cooling a deep yellow solid was obtained filtered and washed with ice cold water yielding 2-(4-Hydroxy)benzoylbenzoic acid as a light yellow solid (4.04 g, 16.6 mmol, 76%); Rf 0.06 (40:60 EtOAc:rhoetrol). mp 228.4- 230.60C. Lit. 2310C.8 IR: 3232, 3163, 1688, 1644, 1577, 1381 cm"1. 1H NMR: (300 MHz, d6-DMSO) delta 6.83 (m, 2H, Ar-H), 7.34 (dd, IH, J = 7.4, 1.3 Hz, Ar-H), 7.50 (m, 2H, Ar-H), 7.58-7.71 (dtd, 2H, J= 22.4, 7.4, 1.3 Hz, Ar-H), 7.95 (dd, IH, J= 7.6, 1.3 Hz, Ar-H), 10.30 (bs, IH, COOH). 13C NMR: (75 MHz, d6-DMSO) delta 115.5, 127.7, 128.6, 129.6, 130, 130.1, 131.9, 132.4, 142.2, 162.4, 167.3, 195.1. LC/MS-ES+ m/z 129.3, 225.1, 264.9, 506.8. |
Yield | Reaction Conditions | Operation in experiment |
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79% | Comparative Example 1 In this example, a prior art process was employed to isolate a PPPBP product. The prior art process included refluxing a mixture of <strong>[77-09-8]phenolphthalein</strong> (20 grams (g)), aniline hydrochloride (20 g), and 60 ml of aniline at a temperature from about 180 C. to about 185 C. for 5 hours under nitrogen. The dark solution was then stirred into a mixture of 100 grams of ice and 70 grams of concentrated HCl. The violet crystalline colored product was filtered off and washed with water. The crystals were then dissolved in ice-cold 10% sodium hydroxide solution. The solution was treated with 0.2 g active carbon, and then filtered. By drop-wise addition of concentrated HCl into the stirred batch, the color changed to a bright pink, then to a pure white, thick slurry with a pH of 3-4. The precipitated <strong>[77-09-8]phenolphthalein</strong> anilide was then washed neutral with water and dried under vacuum at 70 C. The crude crystals gave a melting point of 288-291 C. with a yield of 79%. | |
In water; at 180 - 185℃; for 5h;Inert atmosphere; | This example is in accordance with the commercial process for preparing PPPBP as described in U.S. Patent Publication No. 2005/0288517. Accordingly, a mixture of PP (20 g), aniline hydrochloride (20 g), and 60 mL of aniline was heated under reflux at a temperature of about 180 to about 185C for 5 hours under nitrogen. The resulting dark solution was then stirred into a mixture of 100 grams of ice and 70 grams of concentrated HCl. The crystalline, violet-colored product was filtered off and washed with water. The crystals were then dissolved in an ice-cold 10% (w/v) sodium hydroxide solution. The solution was treated with 0.2 g active carbon, and then filtered. Upon drop-wise addition of concentrated HCl into the stirred filtrate, the color changed to bright pink, then to a pure white, thick slurry having a pH of 3 to 4. The precipitated PPPBP was then washed to neutral with water and dried under vacuum at 700C. The semicrude PPPBP crystals had a melting point of 288 to 2910C. The yield was 79%, based on the weight of the starting PP. At this stage, the crystals have a PP content of 5000 to 7000 ppm.[0073] Double crystallization from ethanol, followed by drying the crystals under vacuum at 150C yielded a PPPBP product having a PP content of 274 pm. In contrast, a single trituration with aqueous methanol yields PPPBP having a PP content of less than 500 ppm.[0074] Alternatively, the semicrude PPPBP crystals (20 g) are triturated with aqueous methanol (72 mL methanol and 8 mL water) at reflux for one hour, cooled to room temperature, filtered, washed with 20 mL of aqueous methanol, washed with 20 mL of hot water (75C), and dried under vacuum for 14 hours at HO0C, to provide a PPPBP product having a PP content of 300 to 350 ppm. Examples IA, IB, 2A, and 3 A[0075] The precipitation procedure of Example 1 and the trituration procedures of Examples 2 and 3 were repeated using a semicrude PPPBP containing 0.4516 wt.% of PP. In Example IA, the precipitation procedure of Example 1 was followed, except that the pH of the solution was adjusted to about 1 to 2. In Example IB, the precipitation procedure of Example 1 was followed, with the pH of the solution being adjusted to 9.5. In Example 2A, the product of Example IA (precipitation at pH of about 1 to 2) was purified using the single trituration procedure of Example 2. In Example 3A, the product of Example IA (precipitation at pH of about 1 to 2) was purified using the double trituration procedure of Example 3.[0076] The wt.% of PP and the yield for each Example is shown in Table 2. The percent yield is based on the weight of semicrude PPPBP. Table 2.[0077] As can be seen from the results shown in Table 2, aqueous methanol trituration can be used to remove PP from semicrude PPPBP containing high amounts of PP. Two sequential methanol triturations are highly effective in producing purified PPPBP having a PP content below about 200 ppm |
Yield | Reaction Conditions | Operation in experiment |
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Ca. 99% | A four necked round bottom flask equipped with overhead stirrer, thermowell, condenser fitted with a Dean-Stark apparatus, and inlet for nitrogen was charged with aniline (117.0 g) and HCl (33.0 mL, 35% cone). The resulting mixture was allowed to stir for 1 h, followed by addition of <strong>[77-09-8]phenolphthalein</strong> (100.0 g). The reaction mixture was then heated slowly to 154C to remove water via the Dean-Stark trap, and subsequently allowed to continue stirring at 154C for 22 h. At this point, a sample of the reaction mixture was analyzed by HPLC for aminophenol (AP) and <strong>[77-09-8]phenolphthalein</strong> (PP) content (AP = 2100 ppm; PP < 1%). The reaction mixture was then cooled to 120C, whereupon water (300 mL) and HCl (154 mL, 35% cone.) were added. The reaction mixture was allowed to stir for 1 h at this temperature, then cooled to rt. The resulting solid was filtered and washed with DI water until the washings were acid free. The solid was then dried in a centrifuge until the moisture content was less than 20% (as measured by KF titration). Yield of PPPBP: -99% (dry weight basis), purity = 98%. | |
92% | With hydrogenchloride; In water; at 155 - 165℃; for 16h; | Synthesis of 2-phenyl-3,3-bis(4-hydroxyphenyl)phthalimidine Concentrated hydrochloric acid (36%, 20.5 mL, 232 mmol) was added dropwise to an aniline (65 mL, 717 mmol) solution of <strong>[77-09-8]phenolphthalein</strong> (31.86 g,100 mmol). Water was removed by distillation while heating the mixture at an internal temperature of 155 to 165C in an oil bath. The reaction solution was analyzed by liquid chromatography while heating the reaction solution with stirring until <strong>[77-09-8]phenolphthalein</strong>, the starting material, disappeared (about 16 hr). Thereafter, the reaction solution was poured into a mixed solution composed of concentrated hydrochloric acid (36%, 51.4 mL) and water (600 mL). The mixture was stirred for 30 min, was filtered, and washed with water to obtain crystals. The crystals were dissolved in an aqueous solution (800 mL) of sodium hydroxide (16.04 g, 401 mmol). Activated carbon (5.22 g) was added thereto, and the mixture was stirred for 1 hr. The activated carbon was removed by filtration. Fresh activated carbon (5.60 g) was then added to the filtrate, and the mixture was stirred for 1 hr. The activated carbon was removed by filtration, and concentrated hydrochloric acid (36%) was then slowly added dropwise to the filtrate until the filtrate became acidic. The mixture was stirred overnight and was then filtered, and the crystals were washed with water until the pH of the washings was no longer acidic (four times). The crystals were dried under vacuum with an oil-sealed rotary vacuum pump. The crystals were added to 150 mL of methanol (99.9%; manufactured by Mitsubishi Gas Chemical Co., Inc.). The mixture was stirred with heating under reflux for 1 hr and was then allowed to cool to room temperature. The precipitated crystals were collected by filtration, were washed with methanol, and were dried to obtain a product (36.32 g, 92.3 mmol, yield 92%) The structure of the compound thus obtained was identified by an NMR spectrum with a nuclear magnetic resonance apparatus (JNM-EX270FT-NMR; manufactured by Japan Electric Optical Laboratory). The NMR spectrum was as shown in . 1H-NMR: (270 MHz, DMSO-d6, internal standard TMS) delta (ppm) 6.66 (d, 4H, J = 8.6 Hz), 6.92-7.01 (m, 6H), 7.14-7.28 (m, 4H), 7.47-7.65 (m, 2H), 7.83 (d, 1H, J = 6.9 Hz), 9.56 (s, 2H) |
91 - 94% | Examples 1 to 3 and Comparative Example AThe <strong>[77-09-8]phenolphthalein</strong> starting material (50 grams) had a purity of 99.27%. The molar ratio of aniline :<strong>[77-09-8]phenolphthalein</strong>:HCl in the reaction mixture was 3:1 :1. The reactions were quenched with 375 milliliters (ml) of 4 wt% aqueous NaOH to form a biphasic system. 1 ,2-dichloroethane was added to the biphasic system and the basic layer was separated. The basic layer was mixed with activated carbon (5 weight % based on the theoretical weight of 2-hydrocarbyl-3,3-bis(4-hydroxyphenyl)phthalimidine) and filtered. Aqueous HCl (10 wt %) was added and a precipitate formed which was isolated by filtration. The precipitate contained 2-hydrocarbyl-3,3-bis(4- hydroxyphenl)phthalimidine and impurities. Data is shown in Table 1. <n="20"/>Table 1The precipitate comprising 2-hydrocarbyl-3,3-bis(4-hydroxyaryl)phthalimidine was further purified using trituration and washing. Ten grams of each precipitate was used for purification. The samples were triturated with 40 ml of methanol: water (90:10, v:v) and washed with 10 ml of methanol: water (90:10, v:v). Trituration was conducted at 7O0C for 30-120 minutes. After the methanol: water wash the solid was washed with 20 ml of water. The results are summarized in Table 2.Table 2As can be seen from the data in Table 2, trituration and wash of the 2-hydrocarbyl- 3,3-bis(4-hydroxyphenyl)phthalimidine products improved their purity while having only minimal yield loss (about 7wt%).Examples 4 to 11In Examples 4 to 11, 100 grams of crude <strong>[77-09-8]phenolphthalein</strong> starting materials having a purity of 95 wt% were used to prepare 2-hydrocarbyl-3,3-bis(4- hydroxyaryl)phthalimidine products. The molar ratio of aniline:<strong>[77-09-8]phenolphthalein</strong>:HCl in the reaction mixture was 3:1 :1. The reaction conditions are shown in Table 3. The reactions were quenched with 4 wt% aqueous NaOH. 1 ,2-dichloroethane was added to the biphasic system and the basic layer was separated. The basic layer was mixed with activated carbon (5 weight % based on the theoretical weight of 2-hydrocarbyl- <n="21"/>3,3-bis(4-hydroxyphenyl)phthalimidine) and filtered. Aqueous HCl was added (10wt%) and a precipitate formed which was isolated by filtration. The precipitate contained crude 2-hydrocarbyl-3,3-bis(4-hydroxyphenyl)phthalimidine and impurities. Results are shown in Table 3.Table 3The crude 2-hydrocarbyl-3,3-bis(4-hydroxyaryl)phthalimidine products obtained above were purified by trituration and washing using the same steps as described above in Examples 1 to 3 to obtain purified 2-hydrocarbyl-3,3-bis(4- hydroxyaryl)phthalimidine products. Methanol: water at different ratios as shown in Table 4 were used as the triturating solvents. The results of the purifications are summarized in Table 4. <n="22"/>As can be seen from the data in Table 4, the purities of the purified 2-hydrocarbyl- 3,3-bis(4-hydroxyphenyl)phthalimidine products obtained using <strong>[77-09-8]phenolphthalein</strong> having a purity of 94 - 95 wt% as starting materials are in the range of 96.77 to 98.41%. The yield loss was 5-7 weight percent.Examples 12 to 19<strong>[77-09-8]Phenolphthalein</strong> starting materials (200 grams) having a purity of 97-98 wt% were reacted with aniline. The molar ratio of aniline:<strong>[77-09-8]phenolphthalein</strong>:HCl was 3:1 :1. The reactions were quenched with 10 wt% HCl to form a slurry. The slurry was filtered to isolate the precipitate and the precipitate was washed with water. Results are shown in Table 5. <n="23"/>Table 5The precipitates were purified by trituration and washing using the same steps as described above. Methanol: water at different ratios as shown in Table 6 were used as triturating solvents. The results are summarized in Table 6.As can be seen from the data in Table 6, the purities of the purified 2-hydrocarbyl- 3,3-bis(4-hydroxyaryl)phthalimidine products obtained were in the range of 99.05 to 99.36% |
69 - 70% | Example 1 In this example, an adduct comprised of aniline and PPPBP was prepared, the crude PPPBP product isolated, and then purified. A mixture of aniline (340 milliliters (ml)) and concentrated HCl (52 ml, 35% concentration) was heated to reflux under stirring. Water was completely removed by forming an azeotrope with aniline (about 20 ml). The mixture was then cooled to 145 C. and <strong>[77-09-8]phenolphthalein</strong> (Formula (III), R2=H)) 80 grams (g) was added. The reaction mixture was maintained at 145 C. for 26 hours under nitrogen. The reaction mixture was then neutralized with sodium bicarbonate (56 g) under stirring at 145 C. for 0.5 hours and the aniline hydrochloride decomposed. Sodium chloride formed during the neutralization and unreacted sodium bicarbonate was filtered off. Toluene (550 ml) was added to the filtrate and the reaction mass cooled to room temperature. The precipitated solids were filtered off and washed with 100 ml of toluene. The wet cake was dried to constant weight at room temperature (24 C.) to get a dry product (i.e., crude adduct) weighing about 139 g. The crude adduct (139 g) was dissolved in sodium hydroxide solution (450 ml, 4% weight by volume in water), heated to 60 C., and toluene (200 ml) was added to this solution. The mixture was stirred and the toluene layer separated from the aqueous layer. The aqueous layer was treated with 8 g activated charcoal, filtered, and washed with water (150 ml). The clear alkaline solution so obtained was neutralized with concentrated HCl (40 ml) in 80 ml of water. The product was filtered off, washed with water to get a neutral pH of about 7, and dried to a constant weight of 74 g at 112 C. The above product (74 g) was then suspended in methanol (360 ml) and refluxed for 1 hr. Solids separated out, which was filtered, washed with methanol (70 ml), and dried to a constant weight of 68.56 g in an oven at 80 C. to provide the final product, which was found by HPLC analysis to have a PPPBP purity of 99.86%. The yield of the isolated product was 69 to 70 percent of theory. The results are shown in Table 1. FIG. 1 illustrates the 1H NMR spectra for aniline. The aromatic protons for aniline, i.e., 10 protons, provide signals in the region delta 6.5 to delta 7.15. FIG. 2 illustrates the 1H NMR spectra for crude PPPBP. The aromatic protons for PPPBP provide signals in the region delta 6.7 to delta 7.9. FIG. 3 illustrates the 1H NMR for PPPBP-Aniline adduct. The signals provided by the aromatic protons of the adduct are at delta 6.7 to 7.95. The signals provided by free aniline in FIG. 1 at delta 6.5 to delta 7.15 are shifted to the region of delta 7.35 to delta 7.65. The chemical shift difference that is observed can be attributed to the deshielding effect for the aniline ring protons because of hydrogen bonding. This may be due the hydrogen bonding between the hydrogen of OH group of PPPBP & the nitrogen of the NH2 group of aniline. In addition to this the integration of the 1H proton signals in FIG. 3 accounts for 27 ring protons, which implies 1 mole PPPBP (17 ring protons)+2 moles Aniline (10 ring protons). Example 2 In this example, the adduct was prepared in accordance with Example 1, wherein the quantity of aniline used was 310 ml. The results are shown in Table 1. Example 3 In this example, crude <strong>[77-09-8]phenolphthalein</strong> product was firs isolated and then purified via adduct formation. In this example, a mixture of aniline (133 milliliters (ml)) and concentrated HCl (26 ml, 35% concentration) was heated to reflux under stirring. Water was completely removed by forming an azeotrope with aniline. About 13 ml of aniline distilled over azeotropically with the water. The mixture was then cooled to 145 C. and <strong>[77-09-8]phenolphthalein</strong> 40 grams (g) was added. The reaction mixture was maintained at 145 C. for 25 hours under nitrogen. The reaction mixture was neutralized by adding sodium bicarbonate (28 g) and under stirring at 145 C. for 0.5 hours and the aniline hydrochloride decomposed. Sodium chloride formed in the neutralization reaction and unreacted sodium bicarbonate were filtered off. Toluene (220 ml) was added to the filtrate and the reaction mass cooled to room temperature (24 C.). The precipitated solids were filtered off and washed with 100 ml of toluene and 100 ml of petroleum ether at 60-80 C. The wet cake was dried to constant weight in an oven at 80 C. to provide 49 g of the product, which was found by HPLC analysis to have a PPPBP purity of 97.91% with <strong>[77-09-8]phenolphthalein</strong> 1.76% and an impurity content of 0.18%. Crude product (45 g) was dissolved in aniline (120 ml) at 150 C. and then cooled to room temperature (24 C.). The product precipitated out after one day. The entire mass was left undisturbed at room temperature for one more day. The solid (adduct) separated was filtered, and washed with 250 ml of toluene to obtain a solid weighing 54 g. The filtrate was left at room temperature for one day and the second crop of solid separated was filtered and washed with 100 m... | |
hydrogenchloride; In water; at 100 - 160℃; for 24 - 48h;Product distribution / selectivity; | Example 1; 100.0 grams (g) (0.3141 mole) of <strong>[77-09-8]phenolphthalein</strong> (having a purity of 99.7 weight percent), 117.0 g (1.25 mole) of aniline, and 32.8 milliliters (ml) of 35 wt % aqueous HCl (0.3141 mole) were combined in a 500 ml four neck round bottom flask fitted with an overhead stirrer, a nitrogen gas inlet, thermowell, and a condenser with Dean-Stark apparatus. A slow stream of nitrogen gas was continuously passed through the flask, and the reaction mixture was heated at 100 to 120 C. for 2 to 3 hours to remove the by-product water (approximately 28 ml). The reaction mixture was then heated at 155 to 160 C. for 22 to 24 hours and allowed to cool to 100 to 110 C. 250 ml of 10 wt % aqueous HCl was then added into the reaction mixture followed by stirring for 2 hours. A precipitate was formed, filtered out, washed 5 times with 100 ml of water (85 C.) (5×100 ml) until free from chloride, and dried, resulting in crude 2-phenyl-3,3-bis(4-hydroxyphenyl)phthalimidine.The crude 2-phenyl-3,3-bis(4-hydroxyphenyl)phthalimidine (120 g) was then dissolved in 700 ml of 4 wt % aqueous NaOH solution, treated with 12 g of activated carbon for 1 hour and filtered. The activated carbon treatment was repeated 3 more times. The filtrate was acidified with 280 ml of 10 wt % aqueous HCl and heated to 70 C. for 1 hour to precipitate 2-phenyl-3,3-bis(4-hydroxyphenyl)phthalimidine, which was filtered out, washed with water until free from chloride and dried. The yield was 117.5 gm or 95%.The precipitate comprising 2-phenyl-3,3-bis(4-hydroxyphenyl)phthalimidine was further purified using trituration and washing. The precipitate was triturated with 470 ml of methanol:water (90:10, v:v) and washed with 120 ml of methanol:water (90:10, v:v). Trituration was conducted at 70 C. for 120 minutes. After the methanol:water wash the solid washed with 120 ml of water. Final yield was 105 g with a purity of 99.94 w %.; Example 2; 100.0 grams (g) (0.3141 mole) of <strong>[77-09-8]phenolphthalein</strong> (having a purity of 99.7 weight percent), 117.0 g (1.25 mole) of aniline, and 32.8 milliliters (ml) of 35 wt % aqueous HCl (0.3141 mole) were combined in a 500 ml four neck round bottom flask fitted with an overhead stirrer, a nitrogen gas inlet, thermowell, and a condenser with Dean-Stark apparatus. A slow stream of nitrogen gas was continuously passed through the flask, and the reaction mixture was heated at 100 to 120 C. for 2 to 3 hours to remove the by-product water (approximately 28 ml). The reaction mixture was then heated at 155 to 160 C. for 22 to 24 hours and allowed to cool to 100 to 110 C. 250 ml of 10 wt % aqueous HCl was then added into the reaction mixture followed by stirring for 2 hours. A precipitate was formed, filtered out, washed 5 times with 100 ml of water (85 C.) (5×100 ml) until free from chloride, and dried, resulting in crude 2-phenyl-3,3-bis(4-hydroxyphenyl)phthalimidine.The crude 2-phenyl-3,3-bis(4-hydroxyphenyl)phthalimidine (120 g) was then dissolved in 630 ml of 4 wt % aqueous NaOH solution. This solution was filtered. To the filtrate, a solution of 8.4 g NaOH in 66 ml water was added and stirred for 15 minutes. This reaction mixture was treated with 12 g of activated carbon for 1 hour and filtered. The activated carbon treatment was repeated 1 more time. The filtrate was acidified with 350 ml of 10 wt % aqueous HCl to precipitate 2-phenyl-3,3-bis(4-hydroxyphenyl)phthalimidine, which was filtered out, washed with water until free from chloride and dried. The yield was 120 g or 96%.The precipitate comprising 2-phenyl-3,3-bis(4-hydroxyphenyl)phthalimidine was further purified using trituration and washing. The precipitate was triturated with 470 ml of methanol:water (90:10, v:v) and washed with 120 ml of methanol:water (90:10, v:v). Trituration was conducted at 70 C. for 120 minutes. After the methanol:water wash the solid washed with 120 ml of water. Final yield was 109 gm of PPPBP with purity of 99.91 w %.; Example 3; 100.0 g (0.3141 mole) of <strong>[77-09-8]phenolphthalein</strong> (having a purity of 99.7 weight percent), 117.0 g (1.25 mole) of aniline and 32.8 ml of 35 wt % aqueous HCl (0.3141 mole) were combined in a 1000 ml four neck round bottom flask fitted with a overhead stirrer, a nitrogen gas inlet, thermowell, and an condenser with Dean-Stark apparatus. A slow stream of nitrogen gas was continuously passed through the flask, and the reaction mixture was heated at 100 to 120 C. for 2 to 3 hours to remove the by-product water (approximately 21 ml). The reaction mixture was then heated at 155 to 160 C. for 22 to 24 hours and allowed to cool to 100 to 110 C. 700 ml of 4 wt % aqueous NaOH solution was then added into the reaction mixture followed by stirring for 2 hours. Free aniline was recovered by extracting the alkaline 2-phenyl-3,3-bis(4-hydroxyphenyl)phthalimidine solution with 200 ml (100 mlX2) of dichloroethane. The lower organic layer was separated out and aniline was recovered after distillation of solvent. The upper aqueous layer was transferred to a... | |
hydrogenchloride; In water; at 140 - 145℃; for 45h;Inert atmosphere;Product distribution / selectivity; | A mixture of PP (50 g), aniline (58.5 g), and concentrated aqueous hydrochloric acid (10 M, 16.4 g) was heated under reflux at a temperature of about 140C to about 145C for 45 hours under nitrogen, with removal of water using a Dean-Stark apparatus. The resulting dark solution was then stirred into a mixture of ice and concentrated HCl. The violet colored, crystalline crude PPPBP product was separated by filtration and washed with water. At this stage, the crude PPPBP typically has a PP content of 0.5 to 0.7 % by weight of the crude PPPBP. In this example, the crude PPPBP had a purity of 99.3139% as determined by HPLC, and a PP content of 0.5378 wt.% (5,378 ppm).[0067] The crude crystals (20 g) were then dissolved in 130 mL of 4% (w/v) sodium hydroxide solution. The solution was treated twice with 2 g each of activated carbon, and then filtered. The filtrate was treated by drop-wise addition of concentrated HCl with stirring. The aqueous base solution changed from a bright pink solution to a pale pink, thick slurry with a pH of 9.5. The slurry was stirred for one hour after the desired pH was attained. The precipitated phthalimidine compound was then filtered, washed with dilute HCl (5 M), and then washed with water until the water washings were neutral, and dried under vacuum at 700C. The semicrude PPPBP crystalline solid was obtained in a yield of 97.9% based on the crude PPPBP crystals, and had a purity of 99.65%, with a PP content of 0.2095 wt.% (2,095 ppm). | |
With pyridine; hydrogenchloride; In water; at 50 - 145℃; for 35h;Dean-Stark; | First, 8.3 ml of 35 wt% aqueous HC1 (0.079 mol) and 28.85 ml (0.316 mol) of aniline were combined in a 250-ml 3 -neck round bottom flask fitted with an overhead stirrer, a thermowell and a condenser with Dean-Stark apparatus. The reaction mixture was heated to about 120C (internal temperature), for about an hour to remove water. The reaction mixture was then cooled to about 50-60C, then 25 g (0.079 mol) of <strong>[77-09-8]phenolphthalein</strong> and pyridine co- catalyst (0.009-0.08 mol) as shown in Table 1 were added. The reaction mixture was heated to 145C (internal temperature) for 48-30 h and allowed to cool to 100-110C. Next, 108 ml of 10% aqueous HCl was then added into the reaction mixture followed by stirring for 1 h. A precipitate was formed, filtered out, washed with water until free from chloride, and dried, resulting in crude PPPBP. The results for different concentrations of the co-catalyst are provided in Table 1. | |
11.82 g | With hydrogenchloride; In water; | A reaction mixture containing PPPBP was obtained via reaction of aniline and <strong>[77-09-8]phenolphthalein</strong> in the presence of hydrochloric acid, as described, for example, in US Patent 8,809,486. After the reaction mixture was cooled to 100C, it was quenched with aqueous hydrochloric acid (150 milliliters (ml)) and water (300 ml). During quenching, PPPBP precipitated out of the reaction mixture. The reaction mixture was kept at 100C for 1 hour (hr) and the resulting slurry was filtered and the solid was washed with 250 ml water. The resultant solid PPPBP (crude PPPBP) was dried at 100C for 5 hrs and analyzed by high pressure liquid chromatography (HPLC) to obtain the amount of aminophenol impurity (AP), <strong>[77-09-8]phenolphthalein</strong> (PP), and PPPBP in weight percent (wt%). Results are provided in Table 1. Dry wt. of crude PPPBP was 118.2 grams |
With hydrogenchloride; In water; for 50h; | The second chemistry step is the reaction of <strong>[77-09-8]phenolphthalein</strong> with aniline catalyzed by hydrochloric acid in a reaction that can be conducted for up to 50 hrs. The reaction mixture is then cooled to room temperature and treated with hydrochloric acid and water. The solid crude product is obtained after filtration and washing with water. Crude PPPBP has aminophenol (AP) as the major impurity. Removal of the AP impurity is performed to reduce the AP concentration to less than 50 parts per million (ppm), and can require multiple steps wherein the crude product is subjected to multiple treatments with activated charcoal in an alkaline medium to remove AP impurity. After charcoal treatment, the PPPBP is then isolated from the base solution by neutralization. Solid PPPBP is recovered by batch filtration. The solid PPPBP is then subjected to methanol trituration for removal of unreacted residual <strong>[77-09-8]phenolphthalein</strong> followed by filtration, hot water wash, and drying. The final PPPBP product is obtained with an overall yield of 89-90% with respect to <strong>[77-09-8]phenolphthalein</strong>. | |
With hydrogenchloride; In water; at 100 - 170℃;Large scale; | 70 kilograms (kg) of <strong>[77-09-8]phenolphthalein</strong> containing 10 wt % water, 98.75 kg of aniline, and 22 kg of HCl (32 wt % in water) were combined in a 200 liter (L) glasslined reactor fitted with an overhead condenser. The reaction mixture was heated at 100-120 C. and passed through a wiped film evaporator to remove water as an aniline-water azeotrope. The reaction mixture was then heated at 170 C. (internal temperature), and continued until the <strong>[77-09-8]phenolphthalein</strong> concentration was measured to be about 1 wt % in the reaction mass. The reaction mass was then allowed to cool to 150-160 C. The reaction mixture was added into another reactor containing about 650 kg of NaOH (7-10 wt % in water). The reaction mixture, once mixed with the aqueous NaOH, was cooled to about 100 C. The resulting alkali solution was treated continuously at the rate of about 70 kg/hour (hr) with aniline at a flowrate of about 40 kg/hr in a structured pack extraction column to remove the aminophenol impurity. The traces of aniline in the aqueous solution were removed by treating the alkali solution with 190 kg of 1,2-dichloroethane (EDC). The aqueous portion of the layer-separated alkali solution was isolated and passed through a packed bed of activated carbon to remove the color and other impurities. The total weight (slurry) was 600 kg. The sample was collected at this point and the semi-pure PPPBP was precipitated using HCl. The resultant semi-pure PPPBP was analyzed by high pressure liquid chromatography (HPLC) to obtain the amount of aminophenol impurity (AP), <strong>[77-09-8]phenolphthalein</strong> (PP), PPPBP, and total impurity in weight percent (wt %). The analysis of semi-pure PPPBP using HPLC is given in Table 2A. |
Yield | Reaction Conditions | Operation in experiment |
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With hydrogenchloride; potassium hydroxide; In methanol; ethanol; water; | Step 4 A solution of 34 g (0.19 mol) of trans-4-butylcyclohexyl acetonitrile, 43 g (0.76 mol) of KOH, and 34 cm3 of water in 190 cm3 of ethanol was refluxed over a hot water bath until the generation of ammonia gas ceased (about 10 hours). Ammonia gas was detected using <strong>[77-09-8]phenolphthalein</strong> test paper. The reaction solution was cooled to room temperature and ethanol was distilled off. The residue was dissolved in 100 cm3 of water. The resulting solution was poured into a beaker containing 100 g of water and 100 cm3 of concentrated hydrochloric acid. The crystals precipitated in the beaker were separated out by filtration and washed with water. The crystals were recrystallized from a solvent mixture of methanol and water to yield 37 g (0.19 mol) of trans-4-butylcyclohexyl acetic acid. |
Yield | Reaction Conditions | Operation in experiment |
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99.86% | With hydrogenchloride; magnesium sulfate; triethylamine; In dichloromethane; water; | EXAMPLE 1 Preparation of <strong>[77-09-8]Phenolphthalein</strong> Bis(methacrylate) A 500-milliliter round bottom flask was charged with 42.49 grams of triethylamine and 200 milliliters of methylene chloride. The charged materials were cooled with stirring to 0 C. to 5 C. Over a 15 minute interval and under a nitrogen atmosphere, 63.66 grams of <strong>[77-09-8]phenolphthalein</strong> was added portionwise to the flask with stirring. The resulting mixture was then warmed to ambient temperature over a 30 minute interval. A 1-liter, 4 necked, round bottom flask equipped with a stirrer, addition flask, nitrogen purge tube and thermometer was purged with nitrogen and charged with 42.86 grams of methacryloyl chloride, 0.1 gram of 4-methoxyphenol and 100 milliliters of methylene chloride. The charged materials were stirred and cooled to 0-5 C. by placing the flask in a salt-ice bath. The mixture of <strong>[77-09-8]phenolphthalein</strong> and triethylamine in methylene chloride contained by the 500-milliliter flask was added to the contents of the one-liter flask, dropwise, through the addition flask over a period of 3 hours while maintaining the temperature of the reaction mixture between 0 C. and 5 C. The reaction mixture was then allowed to warm to room temperature (27 C.) over a period of 16 hours. The flow of nitrogen was discontinued and 200 milliliters of water was added. The reaction mixture was stirred for 20 minutes and then allowed to settle into two liquid layers. The organic phase was separated and sequentially washed once with 200 milliliters of water while stirring for 20 minutes, washed twice with 200 milliliters of cold 5% hydrochloric acid while stirring 20 minutes, and washed once with 200 milliliters of water while stirring 20 minutes. After the final phase separation, the pH of the wash water was 6-7. The organic phase was transferred to an Erlenmayer flask. Ten grams of anhydrous magnesium sulfate and 0.2 gram of animal charcoal were added and the contents of the flask were stirred for 30 minutes. This mixture was then filtered through a cone of magnesium sulfate placed over a Waterman #41 filter paper. The filtered organic phase was transferred to a round bottom flask and methylene chloride was removed under aspirator vacuum (absolute pressure of about 2.7 to about 3.3 kilopascals). The resulting thick, colorless liquid product weighed 90.69 grams indicating a yield of 99.86 percent. Infrared spectroscopy and nuclear magnetic resonance spectrascopy confirmed that the product was <strong>[77-09-8]phenolphthalein</strong> bis(methacrylate). Thin layer chromatography, using methylene chloride as the eluent, Rf =0.1, yielded a single spot. |
Yield | Reaction Conditions | Operation in experiment |
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With sodium hydroxide; N-Bromosuccinimide; In 1,4-dioxane; water; isopropyl alcohol; | EXAMPLE 4 PREPARATION OF 2-(1',2'-TRANS-EPOXYPROPYL)QUINOLINE 0.42 g of N-bromosuccinimide (2.35 mmol) is added in small portions to a solution of 330 mg of 2-propenylquinoline (1.96 mmol) in 12 ml of dioxane and 5 ml of water. After stirring for 9 hours at room temperature, the reaction mixture is poured into water and extracted with ether. The organic phase is dried over sodium sulfate and the ether is evaporated off. To the two intermediate regioisomers thereby obtained, 10 ml of isopropanol and a few drops of phenol-phthalein are added, and the mixture is titrated with 1 M sodium hydroxide solution. The solution is thereafter diluted with 10 ml of water, and a precipitate then forms which is extracted 3 times with ether. The residue obtained after the ether phase has been passed over sodium sulfate and the solvent has been evaporated off is deposited on a silica column (hexane/ethyl acetate, 9:1). |
Yield | Reaction Conditions | Operation in experiment |
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60% | With hydrogenchloride; In tetrahydrofuran; methanol; water; | C. Preparation of tetraethyl-3-(dipropylamino)-propane-1,1-bisphosphonate A solution of N,N-dipropyl-3,3-bis(diethoxyphosphinyl)propionamide (1.25 g, 2.9 mmol) in THF (7.1 ml) was cooled to 0 C., and borane-methylsulfide (0.71 ml, 7.1 mmol) was added via syringe. The reaction was stirred at 0 C. for 20 minutes, then warmed at 65 C. for 3 hours. The reaction mixture was cooled to 0 C. and 6N HCl (6 ml) was added carefully. The solvent was removed m vacuo, and the residue was treated with methanol (5 ml) and concentrated. The residue was dissolved in water (10 ml) and extracted with Et2 O (3*10 ml). The aqueous layer was made basic to <strong>[77-09-8]phenolphthalein</strong> with solid KOH and saturated with NaCl. The product was extracted into dichloromethane (5*20 ml), dried (Na2 SO4) and concentrated to give the title compound (0.71 g, 60%). |
Yield | Reaction Conditions | Operation in experiment |
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87% | With yttrium(lll) nitrate hexahydrate; In acetic acid; at 20℃; for 1h; | Phenol (94 mg, 1 mmol) dissolved in 3 mL glacial acetic acidin a 50 mL test tube was treated with solid Y(NO3)3.6H2O(383 mg, 1 mmol) with constant shaking at RT for 10 min.The reaction was monitored by TLC at 10% EtOAc inPetroleum benzene. Ice-cold water (30 mL) was added to thereaction mixture after completion of reaction and left for 15min. Solid was collected by filtration and washed with water.Solid product isolated in this way was used for analysis withoutfurther purification. Experimental procedure for the synthesisof compounds 2a-2e is mentioned in the SupportingInformation. |
78% | With nitric acid; In acetic acid; at 15 - 20℃; for 6h;Product distribution / selectivity; | A mixture of <strong>[77-09-8]phenolphthalein</strong> (0.062 mol) in acetic acid (290 mL) was stirred at 15 C. Concentrated nitric acid (0.136 mol, 65%) in acetic acid (10 mL) was slowly added to stirring mixture at 15 C. The reaction mixture was further stirred for 6 hours at room temperature and added to ice-water mixture when the yellow colored product precipitated. The product was filtered, thoroughly washed with water and dried. Recrystallization from ethanol with charcoal treatment furnished pure 3,3-bis-(4-hydroxy-3-nitrophenyl)-1-(3H)-isobenzofuranone as pale yellow crystals in 78% yield. IR (KBr): 3262, 1766, 1627, 1538, 1423 cm-1. 1H-NMR (DMSO-d6): delta 9.67 (s, 2H, 2OH), 6.71-7.16 (m, 6H, aromatic), 7.46-7.98 (m, 4H, aromatic) ppm. Mass spectra: m/z 408 (M+). |
Yield | Reaction Conditions | Operation in experiment |
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In iso-butanol; xylene; at 80 - 105℃; | A) Preparation of 3J3'-bis(3,4-dihydro-3-phenyl-2H-1 ,3-benzoxazin-6-yl)-1 (3H)- isobenzofuranoneIn a 22 liters glass jacketed Belatec reactor fitted with an addition funnel, thermocouple and a condensor 3884.1 g (12.2 mol) of phenoplphthalein is charged. Subsequently the reactor is charged with 1721.5 g (59.3 mol) of paraformaldehyde, 2420 ml of xylene and 4840 ml of sec-butanol under stirring (ca. 350 rpm). That reaction mixture is preheated to 80C-82C with stirring.2383.7 g (25.6 mol) aniline is added over a period of 45 min to 1 hour with simultaneous heating to the refluxing point at 94-95C, maintaining intensive refluxing with separation of water.When 25% of the solvents are removed, additionally 600 ml of xylene and 1200 ml sec- butanol are slowly added to the reaction mixture such that the the drop of the reaction temperature is minimized. The xylene/sec.-butanol/water azeotrope distills at a higher temperature as the water is removed, so the temperature must be increased to maintain a steady distillation rate. After the water removal is complete, the condensor is replaced by with a distillation head and a receiver.When the boiling temperature reaches a value of 100-1050C (within 6-7 hours of the initial reflux), the water removal and condensation process is over, and the solvent distillation is started until the temperature of the solution is 120C-122C (no vacuum is applied). At this point the concentration of the solids is determined. At a concentration of 70.5% to 71.5 % of solids the process is over and the product can be discharged or used for the preparation of the laminating composition in the same reactor.Melting point: 98-1030C1 H-NMR (d6 acetone): delta = 4.59 ppm (s); delta = 5.4 ppm (s); delta = 6.5-7.3 ppm (m); delta = 7.5 ppm (m);Infrared spectrum (KBr pill) IR (neat): 3600 cm"1 - 3150 cm"1; 3100 cm"1 - 3000 cm"1; 2950 cm"1; 2850 cm"1; 1750 cm"1; 1600 cm"1; 1450 cm"1; 1220 cm"1; 1090 cm"1; 950 cm"1; 725 cm"1; 650 cm"1. | |
In ethanol; toluene; at 80 - 90℃; for 24.5h;Dean-Stark; | The synthesis of <strong>[77-09-8]phenolphthalein</strong> bis(benzoxazine) was performed according to literature reports. See, P. Yang and Y. Gu, Journal of Polymer Research, 2011, volume 18, pages 1725-1733; P. Yang, X. Wang, and Y. Gu, Journal of Polymer Research, 2012, volume 19, page 9901; and R. Tietz, D. Orser, Y. Blyakhman, M. Bryant, and B.-S. Lin, ?Benzoxazine Compounds Derivated from <strong>[77-09-8]Phenolphthalein</strong> Having Flame-Retardant Properties and a Process for Their Preparation,? European Patent No., EP 1 797 081 B1, 2005. <strong>[77-09-8]Phenolphthalein</strong> (19.91 grams, 0.0626 mole) was added to a 500 milliliter 3-neck flask equipped with a Dean-Stark apparatus and a condenser. The <strong>[77-09-8]phenolphthalein</strong> was allowed to partially dissolve in 45 milliliters toluene at 80 C. for about 30 minutes. To this solution, paraformaldehyde (12.4 grams, 0.4 mole) was added, followed by aniline (13 milliliters, 0.14 moles) and 15 milliliters of ethanol. The reaction was allowed to stir for 24 hours at 85 to 90 C. The solution was allowed to cool to room temperature and the solvent was removed under reduced pressure to yield an oil. The oil was dispersed in small amount of methylene chloride and precipitated into hexane to yield yellow powder (crude yield 39 grams, 114.7%). The crude product was purified using preparatory HPLC in hexane and ethyl acetate solvent. The pure fractions were mixed and concentrated in vacuum to yield a colorless oil which was mixed with methylene chloride and precipitated into hexane to yield a pale off-white solid. 1H NMR spectrum confirmed the formation of pure Phen-BZ as the product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95%. | With sodium hydroxide In ethanol; water | Phenolphthalin (B) Phenolphthalin (B) To a 3 L 3-necked flask containing 60 g of phenolphthalein (A), 450 ml of water and 525 ml of ethanol was added 450 mL of 50% sodium hydroxide solution in ethanol and 300 g of zinc powder. The contents were heated to reflux and maintained at that temperature for 12 hrs. The solution was cooled to room temperature, filtered and acidified until phenolphthalin precipitated as a white powder. This was collected by filtration and dried at 80° C. for 24 hrs at reduced pressure. Yield=95%. m.p.=234°-236° C. |
Yield | Reaction Conditions | Operation in experiment |
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With potassium hydroxide; hydroxylamine hydrochloride; sodium ethanolate; In ethanol; water; | (a) Ethanol (36 ml) and a small amount of <strong>[77-09-8]phenolphthalein</strong> was added to 97% hydroxylamine hydrochloride (2.15 g, 1.5 eq.) and then a solution of potassium hydroxide in ethanol (1 g/5 ml) was added dropwise with ice cooling to neutralize the mixture. Ethyl trifluoroacetoacetate (3.68 g, 0.02 mole) was added to this solution and the mixture was reacted with stirring under reflux for 4 hours. After completion of the reaction, water (300 ml) was added at room temperature and the mixture was extracted continuously for 10 hours with diethyl ether. After the ether layer was dried with anhydrous sodium sulfate, diethyl ether was distilled off. Dry ethanol (20 ml) was added to the residue and a solution of sodium ethoxide in ethanol (1 g Na/20 ml) was added dropwise with ice cooling until <strong>[77-09-8]phenolphthalein</strong> was colored. The solution was evaporated under reduced pressure to remove ethanol, and benzene was added to the residue. Precipitate was filtered off to give 1.99 g (51.5 % as monohydrate) of 3-trifluoromethyl-5-hydroxyisoxazole sodium salt which can be represented by the formula: STR6 as colorless granular crystals. The filtrate was purified by subjecting it to silica gel chromatography to give 0.97 g (24.4%) of ethyl trifluoromethylacetoacetate oxime of the formula: | |
With potassium hydroxide; hydroxylamine hydrochloride; sodium ethanolate; In ethanol; water; | (a) Ethanol (36 ml) and a small amount of <strong>[77-09-8]phenolphthalein</strong> was added to 97 % hydroxylamine hydrochloride (2.15 g, 1.5 eq.) and then a solution of potassium hydroxide in ethanol (1 g/5 ml) was added dropwise with ice cooling to neutralize the mixture. Ethyl trifluoroacetoacetate (3.68 g, 0.02 mole) was added to this solution and the mixture was reacted with stirring under reflux for 4 hours. After completion of the reaction, water (300 ml) was added at room temperature and the mixture was extracted continuously for 10 hours with diethyl ether. After the ether layer was dried with anhydrous sodium sulfate, diethyl ether was distilled off. Dry ethanol (20 ml) was added to the residue and a solution of sodium ethoxide in ethanol (1 g Na/20 ml) was added dropwise with ice cooling until <strong>[77-09-8]phenolphthalein</strong> was colored. The solution was evaporated under reduced pressure to remove ethanol, and benzene was added to the residue. Precipitate was filtered off to give 1.99 g (51.5 % as monohydrate) of 3-trifluoro-methyl-5-hydroxyisoxazole sodium salt which can be represented by the formula: as colorless granular crystals. The filtrate was purified by subjecting it to silica gel chromatography to give 0.97 g (24.4 %) of ethyl trifluoromethylacetoacetate oxime of the formula: CF3C(NOH)CH2COOC2H5. |
Yield | Reaction Conditions | Operation in experiment |
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With sodium hydroxide; acetic acid; In water; toluene; | A significant infrared maximum appeared at 1710 (C=O; s) cm-1. The remaining toluene layer from above was evaporated to dryness to obtain 26.0 g of a sticky pale blue-colored solid. A ten gram aliquot of the solid was slurried in 50.0 ml of hot toluene, the undissolved solid collected by filtration after cooling to room temperature and washed with 10.0 ml of toluene and dried in vacuo to obtain 5.8 g of an iron complex of 2-[4,4'-bis(dimethylamino)benzhydryl]-5-dimethylaminobenzoic acid as a gray-colored solid. The thus obtained iron complex was slurried in water and rendered alkaline to phenolphthalein test paper by the addition of five percent aqueous sodium hydroxide, heated to approximately 90 C., cooled to approximately 30 C. and filtered twice through diatomaceous earth. The slightly hazy filtrate was slowly made acid to approximately pH 5 by the addition of dilute aqueous acetic acid. The solid which separated was collected by filtration, washed with water and air dried to obtain 2-[4,4'-bis(dimethylamino)benzhydryl]-5-dimethylaminobenzoic acid (Formula III: R=CH3; X=H; Y=Z=4-(CH3)2 NC6 H4) as a light gray-colored solid which melted over the range 203-210 C. The infrared spectrum had a significant maximum at 1710 (C=O; s) cm-. The nuclear magnetic resonance spectrum was concordant with the assigned structure. The combined toluene filtrate and wash from above was evaporated to obtain 4.4 g of 3,3-bis(4-dimethylaminophenyl)-6-dimethylaminophthalide (Formula I: R=CH3; X=H; Y=Z=4-(CH3)2 NC6 H4), a dark blue-colored solid. A significant infrared maximum appeared at 1759 (C=O; s) cm-1. The nuclear magnetic resonance spectrum was consistent with the assigned structure. A toluene solution of the product spotted on silica gel develops a blue-colored image. |
Yield | Reaction Conditions | Operation in experiment |
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In methanol | 18 EXAMPLE 18 EXAMPLE 18 To a solution of α-bromoisovaleric acid (2 g, 0.110 mole) and 5 ml of methanol is added one drop of phenolphthalein and then sufficient sodium hydroxide/methanol until adjusted to neutral pH. The solvent is then stripped off and p-chloroaniline (7 g, 0.055 mole) added. The mixture is melted in a 100° bath and stirred at 100° for 3 hours. The mixture is cooled and taken up in ether, and 10% aqueous sodium hydroxide is added. The aqueous phase is acidified to pH 4 and extracted with ether. The ether extracts are combined and washed with brine, dried over sodium sulfate and stripped to yield N-(p-chlorophenyl)valine. Following the procedure of Example 1, part A, N-(p-chlorophenyl)valine is converted to the acid chloride and then reacted with m-phenoxybenzyl alcohol to yield the m-phenoxybenzyl ester of N-(p-chlorophenyl)valine. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With hydroxylamine hydrochloride; hydroxylamine; In methanol; | Example 2 Disodium salt of N-phosphonomethylglycylhydroxamic acid To a solution of 27.5 g (0.15 mole) of methyl N-phosphonomethylglycinate in 700 ml of methanol is added a solution of 0.3 mole of hydroxylamine in 300 ml of methanol, which is obtained by adding a solution of 6.9 g (0.3 gram-atoms) of sodium in 200 ml of methanol to a suspension of 21 g (0.3 mole) of hydroxylamine hydrochloride and filtering off the NaCl precipitate. To this solution is further added a solution of 6.9 g (0.3 gram-atoms) of sodium in 250 ml of methanol until the reaction solution is alkaline to <strong>[77-09-8]phenolphthalein</strong>. After a reaction time of 16 hours the disodium salt of N-phosphonomethylglycylhydroxyamic acid is obtained in 95% yield in the form of a finely crystalline colourless powder which does not melt below 210 C. (compound 2). Analysis: C3 H7 N2 Na2 O5 P--calculated: C 15.8, H 3.1, N 12.3, Na 20.2, P 13.6; found: C 15.6, H 3.3, N 11.5, Na 19.5, P 13.0, Cl 0.3. |
Yield | Reaction Conditions | Operation in experiment |
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38% | With sodium hydroxide; In water; | EXAMPLE 2 To a stirred solution containing 21.3 (0.1 mol) of disodium-N-phosphonomethylglycine in water at a temperature of 10-15 C. was slowly added 17.5 g (0.105 mol) of 4-chloro-2-butynyl chloroformate. A 50% sodium hydroxide solution was slowly added to the reaction mixture to a <strong>[77-09-8]phenolphthalein</strong> endpoint. The addition of the sodium hydroxide solution was repeated until the <strong>[77-09-8]phenolphthalein</strong> endpoint was stable. The resulting mixture was extracted with diethyl ether. The layers were separated and the aqueous layer was acidified with hydrochloric acid, then passed over acid Dowex-50 ion exchange resin. The elude was concentrated in vacuo yielding a residual gum which was dried over potassium hydroxide pellets (at 1 mm Hg) to yield N-[(4-chloro-2-butynyl)oxy]carbonyl-N-phosphonomethylglycine (11.3 g; 38% yield) as a tan glass having the following analysis: Calculated: Cl, 11.83; P, 10.34. Found: Cl, 12.82; P, 11.03. |
Yield | Reaction Conditions | Operation in experiment |
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With potassium hydroxide; hydroxylamine hydrochloride; In ethanol; | Preparation 24 To a suspension of hydroxylamine hydrochloride (22.3 g) in ethanol (25 ml) was added a <strong>[77-09-8]phenolphthalein</strong> indicator (0.3 ml), and thereto was added dropwise a solution of potassium hydroxide (23.1 g) in ethanol (185 ml) little by little until dark red color of the mixture changed into pale red, followed by stirring for an hour. After removal of the potassium chloride by filtration, to the filtrate was added ethyl 2-cyano-2-methoxyiminoacetate (50 g), followed by stirring at 20 to 30 C. for 3 days. Removal of the solvent gave ethyl 3-amino-3-hydroxyimino-2-methoxyiminopropionate, which was dissolved in dioxane (200 ml) and then evaporated. |
Yield | Reaction Conditions | Operation in experiment |
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With hydrogenchloride; sodium hydroxide;palladium on charcoal catalyst; In acetone; | EXAMPLE XI 2,7-Bis(piperidinomethyl)fluorene A mixture of 6.15 g (0.016 mole) of 2,7--bis(piperidinomethyl)fluorene-9-ol, 12.1 ml of 10% hydrochloric acid, sufficient deionized water to bring the total volume to 150 ml, and 3.0 g of 10% palladium on charcoal catalyst is placed in a Paar hydrogenation apparatus and hydrogenated at room temperature for a period of 2 hours and 45 minutes. The resulting mixture is filtered and sufficient 20% sodium hydroxide solution is added to render the mixture basic to <strong>[77-09-8]phenolphthalein</strong> indicator. The reaction mixture is extracted four times with chloroform, the extracts combined, washed twice with deionized water, treated with charcoal, filtered, and the major portion of the solvent removed at atmospheric pressure. The residue is recrystallized twice from methanol and once again from acetone yielding 2,7-bis(piperidinomethyl)fluorene having a m.p. 135-6C, lambdamax0.1N HCl 270, and E1cm1% 807. |
Yield | Reaction Conditions | Operation in experiment |
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68% | With hydroxylamine hydrochloride; In methanol; water; acetic acid; | Octanedioic acid adamantan-1-ylamide hydroxyamide (17) To a first solution of hydroxylamine hydrochloride (66 mg, 0.950 mmol) and <strong>[77-09-8]phenolphthalein</strong> (0.5 mg) in methanol (3 mL), was added dropwise a second solution of sodium metal (33 mg, 1.435 mmol) in methanol (3 mL) via additional funnel until a pink endpoint was reached and precipitate appeared. To the reaction mixture was added a solution of 7-(adamantan-1-yl-carbamoyl)-heptanoic acid methyl ester (152 mg, 0.474 mmol) in methanol (4 mL) was added, followed by the remainder of the second solution of sodium metal in methanol. The resulting reaction was allowed to stir for 24 hours, then the reaction mixture was diluted with water (15 mL), followed by glacial acetic acid (0.2 mL) with stirring. The resulting precipitate was suction filtered and rinsed using water, then dried at room temperature under vacuum to provide a crude residue which was purified by recrystallization from dichloromethane/hexane to provide Compound 17 (104 mg, 68% yield). 1H NMR (300MHz, CD3OD) delta 7.31 (br s, 1H), 2.09 (t, J=7.5 Hz, 2H), 2.08-1.98 (m, 11H), 1.71 (m, 6H), 1.59 (m, 4H), 1.33 (m, 4H). 13C NMR (75 MHz, CD3OD) delta 175.7, 173.1, 52.8, 42.5, 38.0, 37.7, 33.9, 31.1, 30.00, 29.96, 27.2, 26.8. |
Yield | Reaction Conditions | Operation in experiment |
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88% | With iodine; at 20℃; for 0.8h;Neat (no solvent); Air atmosphere; | General procedure: Iodine (5.1 mg, 0.02 mmol) was added to phenol 1l (0.148 g, 1 mmol) or alcohol 3h (0.242 g, 1 mmol), followed by addition of HMDS (0.089 g, 0.55 mmol); the mixture was stirred at room temperature until the complete consumption of the starting material (TLC check). The crude reaction mixture was dissolved in 4 mL of hexane/TBME and stirred with the finely powdered Na2S2O3 until the disappearance of iodine. From this point on, two different scenarios are possible: a) The solids were filtered off and the solvent evaporated under the reduced pressure, yielding the crude product. In numerous cases, such products were practically pure; column chromatography and/or distillation improved their quality only slightly. b) A solution of a product in hexane/TBME mixture could be directly subjected to the column chromatography, without filtration of the solids. Caution: Although we experienced no problems when performing these reactions, care should taken due to the potential formation of NI3. |
Yield | Reaction Conditions | Operation in experiment |
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Synthesis Example 2> Synthesis of _ 2-(4-Methylphenyl)-3,3-bis(4-hydroxyphenyl)phthalimidine (abbreviated to BisP-PI-NpTol) p-Toluidine (31.8 g, 717 mmol) was heated to 80C for melting, and concentrated hydrochloric acid (36%, 20.5 mL, 232 mmol) was added dropwise thereto. Thereafter, <strong>[77-09-8]phenolphthalein</strong> (31.8 g, 100 mmol) was added, and water was removed by distillation from the mixture while heating the mixture at an internal temperature of 155 to 165C in an oil bath. The reaction solution was analyzed by liquid chromatography while heating the reaction solution with stirring until <strong>[77-09-8]phenolphthalein</strong>, the starting material, substantially disappeared (about 18 hr; HPLC assay: <strong>[77-09-8]phenolphthalein</strong> 4 area%, p-toluidine 20 area%, product 76 area%). The reaction solution was poured into a mixed solution composed of concentrated hydrochloric acid (36%, 51.4 mL) and water (600 mL). The mixture was stirred for 3 days, was filtered, and was washed with water to obtain crystals. The crystals were dissolved in an aqueous solution (1 L) of sodium hydroxide (10.06 g, 252 mmol). Activated carbon (5.01 g) was added thereto, and the mixture was stirred for 1 hr. The activated carbon was removed by filtration. Fresh activated carbon (5.43 g) was then added to the filtrate, and the mixture was stirred for 1 hr. The activated carbon was removed by filtration, and concentrated hydrochloric acid (36%) was then slowly added dropwise to the filtrate until the filtrate became acidic. The mixture was stirred overnight and was then filtered, and the crystals were washed with water until the pH of the washings was no longer acidic (four times). The crystals were dried under vacuum with an oil-sealed rotary vacuum pump to obtain a product. L-7000 series, D-200 Chromatointegrator, manufactured by Hitachi, Ltd. was used in the liquid chromatography (TSKgel ODS-120T column manufactured by Tosoh Corporation). An acetonitrile-water mixed solvent was used as a developing solvent (flow rate 1 ml/min). The structure of the compound thus obtained was identified by an NMR spectrum in the same manner as described above. The NMR spectrum was as shown in Fig. 2. 1H-NMR: (270MHz, DMSO-d6, internal standard TMS) delta (ppm) 2.20 (s, 3H), 6.45 (d, 1H, J = 7.9Hz), 6.64 (d, 4H, J = 8.6Hz), 6.73-6.83 (m, 2H), 6.90-7.05 (m, 5H), 7.23 (d, 1H, J = 7.6Hz), 7.43-7.63 (m, 2H), 7.79 (d, 1H, J = 7.3Hz), 9.55 (s, 2H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
32% | With sodium hydride; In tetrahydrofuran; mineral oil; at 20℃; for 240h;Inert atmosphere; Cooling with ice; | Compound 4 (1.00 g, 1.73 mmol) and <strong>[77-09-8]phenolphthalein</strong> (2) (0.26 g, 0.85 mmol) were dissolved in 100mL of dry THF under an argon atmosphere in a 250 mL three-necked round-bottomed flask. The reaction mixture was cooled in an ice-bath and NaH (60% oil suspension, 0.13 g, 0.325 mmol) in 50 mL of dry THF was quickly added to a stirred solution under an argon atmosphere. The reaction mixture was stirred for 10days at room temperature and the reaction followed on TLC silica gel plates using n-hexane-THF (3:2) solvent system as eluent. Two products were observed on TLC. The reaction mixture was filtered to remove the formed sodium chloride and then solvent was removed under reduced pressure. The resulting colourless oily product was subjected to column chromatography using n-hexane-THF (2:1) solvent system as eluent. The first product was starting material 4, (0.11 g, 11%), Rf=0.7. The second product was compound 8, (0.38 g, 32%, mp>250C), Rf=0.52. Anal. Calc. for 8, C68H60Cl2N14O4P6, (M, 1394): C, 58.59; H, 4.34; N, 14.07. Found: C, 58.72; H, 4.23; N, 14.36%. MS (ESI) m/z (%): 1395,08 (100) [M+H]+. 13C NMR ((126MHz, CDCl3, ppm): delta 169.43 (s, C16), 151.73 (s, C10), 149.71 (d, 2JPC=6.70Hz, C1), 150.43 (d, 2JPC=6.80Hz, C5), 137.56 (s, C12), 134.88 (s, C8), 129.73 (s, C13), 128.62-128.38 (C4, C3), 127.30 (s, C7), 125.45 (s, C6), 125.20-124.15 (C11, C14, C15), 118.70 (s C2), 90.35 (s, C9). |
Yield | Reaction Conditions | Operation in experiment |
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34% | With sodium hydride; In tetrahydrofuran; mineral oil; at 20℃; for 144h;Inert atmosphere; Cooling with ice; | Compound 5 (1.00 g, 1.54 mmol) and <strong>[77-09-8]phenolphthalein</strong> (2) (0.24 g, 0.78 mmol) were dissolved in 100mL of dry THF under an argon atmosphere in a 250 mL three-necked round-bottomed flask. The reaction mixture was cooled in an ice-bath and NaH (60% oil suspension, 0.12 g, 3.0 mmol) in 40 mL of dry THF was quickly added to a stirred solution under an argon atmosphere. The reaction mixture was stirred for 6days at room temperature and the reaction followed on TLC silica gel plates using n-hexane-THF (5:2) solvent system as eluent. Two products were observed on TLC. The reaction mixture was filtered to remove the formed sodium chloride and then solvent was removed under reduced pressure. The resulting colourless oily product was subjected to column chromatography using n-hexane-THF (5:2) solvent system as eluent. The first product was starting material 5, (0.1g, 10%), Rf=0.71. The second product was the compound 9, (0.40g, 34%, highly viscous oily), Rf=0.19. Anal. Calc. for 9, C68H52Cl2N6O4P6S8, (M, 1530): C, 53.37; H, 3.42; N, 5.49. Found: C, 53.64; H, 3.53; N, 5.66%. MS (ESI) m/z (%): 1531,47 (100) (M+H)+. 13C NMR ((126MHz, CDCl3, ppm): delta 169.35 (s, C16), 151.60 (s, C10), 150.51 (d, 2JPC=9.37Hz, C5), 137.72 (s, C12), 135.80 (s, C4), 134.35 (s, C8), 129.65 (s, C13), 129.50-129.21 (C2), 128.50 (s, C3), 127.70 (d, 2JPC=7.01Hz, C1), 126.20-124.00 (C7, C11, C14, C15), 121.23 (d, 3JPC = 5.71Hz, C6), 90.65 (s, C9). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48.53% | With sodium hydride; In tetrahydrofuran; mineral oil; at 20℃; for 144h;Inert atmosphere; Cooling with ice; | Compound 6 (1.00 g, 1.56 mmol) and <strong>[77-09-8]phenolphthalein</strong> (2) (0.24 g, 0.78 mmol) were dissolved in 100 mL of dry THF under an argon atmosphere in a 250 mL three-necked round-bottomed flask. The reaction mixture was cooled in an ice-bath and NaH (60% oil suspension, 0.06 g, 2.4 8mmol) in 40 mL of dry THF was quickly added to a stirred solution under an argon atmosphere. The reaction mixture was refluxed for 10 days and the reaction followed on TLC silica gel plates using n-hexane-THF (5:2) solvent system as eluent. Two products were observed on TLC. The reaction mixture was cooled and filtered to remove the formed sodium chloride and then solvent was removed under reduced pressure. The resulting colourless oily product was subjected to column chromatography using n-hexane-THF (5:2) solvent system as eluent. The first product was starting material 6, (0.01g, 1.16%), Rf=0.67. The second product was the compound 10, (0.57g, 48.53%, highly viscous oily), Rf=0.1. Anal. Calc. for C80H62N6O14P6, (M, 1517,16): C, 63.33; H, 4.12; N, 5.54. Found: C, 63.54; H, 4.45; N, 5.68%. MS (ESI) m/z (%): 1518,26 (100) (M+H)+. 13C NMR ((126MHz, CDCl3, ppm): delta 169.45 (s, C16), 151.83 (s, C10), 150.71 (d, 2JPC=7.41 Hz, C1), 150.55 (m, C5), 137.10 (s, C12), 134.31 (s, C8), 129.65-129.40 (C13, C4, C3), 128.31 (s, C7), 125.03 (d, 3JPC=7.36Hz, C6), 126.17-124.15 (C11, C14, C15), 120.98 (d, 3JPC=7.47Hz, C2), 90.77 (s, C9). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
11.41% | With sodium hydride; In tetrahydrofuran; mineral oil; at 20℃; for 120h;Inert atmosphere; Cooling with ice; | Compound 3 (1.0 g, 1.5 mmol) and <strong>[77-09-8]phenolphthalein</strong> (2) (0.24 g, 0.75 mmol) were dissolved in 100mL of dry THF under an argon atmosphere in a 250 mL three-necked round-bottomed flask. The reaction mixture was cooled in an ice-bath and NaH (60% oil suspension, 0.13 g, 3 mmol) in 40mL of dry THF was quickly added to a stirred solution under an argon atmosphere. The reaction mixture was stirred for 5days at room temperature and the reaction followed on TLC silica gel plates using n-hexane-THF (2:1) solvent system as eluent. Two products were observed on TLC. The reaction mixture was filtered to remove the formed sodium chloride and then solvent was removed under reduced pressure. The resulting colourless oily product was subjected to column chromatography using n-hexane-THF (2:1) solvent system as eluent. The first product was starting material 3, (0.11 g, 12%), Rf=0.87. The second product was compound 7, (0.135 g, 11.41 %, highly viscous oily), Rf=0.46. Anal Calc. for 7, C76H68Cl6N10O4P6, (M, 1584): C, 57.63; H, 4.33; N, 8.84. Found: C, 57.72; H, 4.42; N, 8.96%. MS (ESI) m/z (%): 1585,01 (100) [M+H]+. 13C NMR (126MHz, CDCl3, ppm): delta 169.30 (s, C16), 151.63 (s, C10), 150.45 (d, 2JPC=9.41Hz, C5), 138.17 (s, C12), 136.06 (s, C1), 134.45 (s, C8), 129.68 (s, C13), 129.03 (s, C3), 128.80 (s, C2), 128.52 (s, C4), 127.73 (d, 3JPC=4.30Hz, C6), 126.50-124.20 (C7, C11, C14, C15), 90.67 (s, C9), 48.29 (broad, NCH2). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | In neat (no solvent); for 0.05h;Microwave irradiation; Green chemistry; | General procedure: In an Erlenmeyer flask, we reacted the 1(eq) of hydroxyl compound with 1.1(eq) of (Boc)2O in the absence of any catalyst and any solvent under microwave irradiation in 300W. The reaction was monitored by TLC after 3-5min. 5 cm3 of diethyl ether was added to the mixture, the resulting tert-butanol was freely soluble in diethyl ether and the O-Boc product was crystallized. Purification of the product was accomplished by recrystallization from diethyl ether to give the O-Boc derivatives in good to excellent yields. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | With trifluoroacetic anhydride; In dichloromethane; acetonitrile; at 25℃; for 1h; | General procedure: In a reaction flask, 4-tert-butylphenol (30 mg, 0.20mmol) and 1a (51 mg, 0.24mmol) were dissolved in dichloromethane (2 mL). Trifluoroacetic anhydride (33 L, 0.24mmol) was added to the solution at 25 C. After being stirred for 30 min, the mixture was filtered through a pad of alumina and the filtrate was concentrated. Chromatographic purification on silica gel (hexane/CH2Cl2 = 5/1) yielded 5-(tert-butyl)-2-methylsulfanyl-3-phenylbenzo[b]furan (2a, 51 mg, 0.17mmol, 87%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With hexamethylenetetramine; for 8h;Reflux; | The intermediate (compound 1) was synthesized according to the previously reported procedure [36]. A solution of <strong>[77-09-8]phenolphthalein</strong> (0.5 g, 1.57 mmol) and hexamethylenetetramine (HMTA, 0.66 g, 4.71 mmol) in trifluoroacetic acid (40 mL) was refluxed for 8 h. After the reaction mixture was cooled to room temperature, a solution of HCl(1.0 M, 100 mL) was added to resulting mixture, and then extracted with dichloromethane (100 mL). The organic layer was washed with water three times and saturated brine once, and was dried over sodium sulfate. Removal of the solvent gave white solid. The crude product was recrystallized from a mixture of ethanol/water. Yield: 75%; 1H NMR (400 MHz, 25 C, DMSO-d6): delta 11.04 (s, 2H, ArOH), 10.20 (s, 2H,CHO),7.91 (d, 1H, J=7.74 Hz, ArH), 7.79-7.76 (m, 2H, ArH), 7.65 (t,1H, J=7.52 Hz, ArH), 7.51 (d, 2H, J=2.60 Hz, ArH), 7.43 (d, 1H,J=2.60 Hz, ArH), 7.41 (d, 1H, J=2.60 Hz, ArH), 7.02 (d, 2H,J=8.73 Hz, ArH). |
70% | With hexamethylenetetramine; for 12h;Inert atmosphere; Reflux; | Dialdehyde derivative of <strong>[77-09-8]phenolphthalein</strong> (compound PP) was prepared following the reported method with some minor modification as depicted below [61]. To a solution of <strong>[77-09-8]phenolphthalein</strong> (0.75g, 2.35mmol) in trifluoroacetic acid (60mL) on ice was slowly added hexamethylenetetramine (0.987g, 7.05mmol) and mixed the solution for 10min. Then the solution was slowly warmed and was refluxed for 12h under nitrogen gas. After cooling the mixture to room temperature, a solution of HCl (1.0M, 150mL) was added and extracted with chloroform (100mL). Finally, CHCl3 layer was washed by using deionized water several times and was dried over Na2SO4. With the removal of the CHCl3, a pale-yellow solid was obtained. The final product to gain the purer compound was again crystallized from a mixture of water/ethanol. Yield 70%; 1H NMR [400MHz, CDCl3]: delta 11.25 (s, 2H, ArOH), 9.95 (s, 2H, CHO), 8.03 (d, 1H, J=7.59Hz, ArH), 7.81 (t, 2H, J=7.52Hz, ArH), 7.64 (t, 1H, J=7.51Hz, ArH), 7.54 (d, 2H, J=2.02Hz, ArH), 7.47 (d, 1H, J=2.09Hz, ArH), 7.44 (d, 1H, J=2.09Hz, ArH), 7.01 (d, 2H, J=8.78Hz, ArH). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
First, we prepared the catalyst based on anhydrousZnCl2. ZnCl2 was melted on a metal spoon over an alcoholburner fl ame. The melt was heated until bubbles ceased toevolve (?10 min), after which it was cooled, and the cakewas ground in a mortar. The condensation was performedin two steps using nitrobenzene as solvent. First, 4.9 g(0.052 mol) of phenol was added to 18.6 mL (0.18 mol) of nitrobenzene in a metal crucible, after which 5.6 g(0.052 mol) of o-cresol was added, and the mixture washeated to 50-60 and stirred until the phenols dissolvedcompletely. Then, 16.5 g (0.11 mol) of phthalic anhydridewas added, the mixture was stirred, and 14.2 g (0.104 mol)of anhydrous powdered ZnCl2 was added. In the secondstep, the temperature was raised to 120-130, and themixture was heated for 4 h with intermittent stirring witha putty knife. The following reactant ratio was used in thesynthesis: phthalic anhydride : phenol : ZnCl2 : o-cresol =2.15 : 1.0 : 2.0 : 1.0 ; phenol : nitrobenzene = 1.0 : 3.4. Theproduct yield after purifi cation was 34.0% (5.9 g). Theproduct contained (wt %) 15.0 PP, 34.7 CP, and 50.3 CPP |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49% | In chlorobenzene; at 132℃; for 15h;Inert atmosphere; Schlenk technique; | 1,1?-Di(1-propynyl)ferrocene (1,18 200 mg, 0.8 mmol) and (S)-(-)-1,1?-bi(2-naphthol) (5, 650 mg, 2.3 mmol) in chlorobenzene (20mL) were heated for 16 h at 132 C. After cooling to 23 C themixture was filtered through a frit covered with silica gel (10 ×3 cm). After washing of the frit with CH2Cl2 (3 × 30 mL) thesolvent was removed at reduced pressure, and the brown-blacksolid obtained was purified by column chromatography [SiO2,30 × 3 cm, PE-CH2Cl2 (2:1) to pure CH2Cl2]. Compound 6 (200mg, 0.4 mmol, 47%) was obtained as a brown solid (mp 106-108C). IR: nu = 3518 (w, OH), 3056 (w), 2954 (w), 1620 (w), 1591(m), 1506 (w), 1458 (w), 1430 (w), 1380 (w), 1330 (w), 1255(m), 1229 (s), 1169 (w), 1145 (m), 1121 (m), 1074 (s), 1025 (w),1001 (w), 974 (w), 956 (w), 930 (w), 892 (w), 860 (w), 837 (w),810 (s, Ar), 747 (s), 667 (w), 616 (w) cm-1. 1H NMR (400 MHz,CDCl3): delta = 1.64 (s, 3 H, CH3), 1.88-1.89 (d, J = 1.5 Hz, 3 H, CH3),3.94 (m, 1 H, CpH), 4.01 (m, 1 H, CpH), 4.08 (m, 2 H, CpH), 4.24(m, 2 H, CpH), 4.32 (m, 1 H, CpH), 4.34 (m, 1 H, CpH), 4.86 (m, 1H, OH), 6.05 (q, J = 1.3 Hz, 1 H, CH=C), 7.07-7.15 (m, 3 H, CArH),7.28-7.41 (m, 4 H, CArH), 7.43-7.48 (m, 1 H, CArH), 7.77-7.84 (m,2 H, CArH), 7.92-8.03 (m, 2 H, CArH) ppm. 13C NMR (100.6 MHz,CDCl3): delta = 15.8 [C(OAr)=CCH3], 25.4 (CH=CCH3), 69.5 (CCpH),69.88 (CCpH), 69.99 (CCpH), 70.02 (CCpH), 70.4 (CCpH), 70.5 (CCpH),70.8 (CCpH), 71.1 (CCpH), 75.5 (CCpH), 77.9 (CCpH), 115.1 (CArC),115.2 (CArC), 116.3 (CArH), 117.7 (CArH), 123.5 (CArH), 124.1(CArH), 124.4 (CH=C), 124.6 [C(OAr)=CCH3], 124.8 (CArH), 125.4(CArH), 126.5(CArH), 127.4 (CArH), 128.17 (CArH), 128.19 (CArH),129.4 (CArC), 129.8 (CArC), 130.1 (CArH), 130.9 (CArH), 134.2(CArC), 134.3 (CArC), 136.4 (CH=C), 145.6[C(OAr)=CCH3], 151.5(CArO), 153.5 (CArO) ppm. HRMS: m/z calcd for C36H28FeO2 [M+]:548.1439; found: 548.1448. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60.9% | In ethanol; at 75℃; for 6h; | At room temperature pyrene amine (4.34g, 20.0mmol), <strong>[77-09-8]phenolphthalein</strong> (3.18g, 10.0mmol) was added to a three-neck flask, stirred and dissolved in 100ml of ethanol. Paraformaldehyde (1.2g, 40.0mmol) was added portionwise three-neck flask, kept stirred to mix, and then gradually warmed to 75 reflux. Reaction was stopped after 6 hours, allowed to stand for cooling to obtain a red solution. After 1mol / LNaOH, deionized water, ethanol was removed by rotary evaporation, followed by vacuum dried for 24 hours, the resulting solid product is the amine pyrene - <strong>[77-09-8]phenolphthalein</strong> benzoxazine, yield 60.9%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1120 g | With 1-methyl-pyrrolidin-2-one; In water; at 82℃; for 8h;Large scale; | Example 1 (0172) The synthesis of the monomer building block according to the invention is effected according to FIG. 1. (0173) A solution of 2 kg (20.2 mol) of N-methylpyrrolidone (NMP) and 1273.3 g (4 mol) of <strong>[77-09-8]phenolphthalein</strong> is initially introduced into a reactor having a plane ground joint. With stirring, 2 liters of water and then 18 mol of a 40% strength aqueous methylamine solution are added. On addition of the methylamine, the reaction solution acquires a violet discoloration. With the use of a dry ice cooler, stirring is then continued for 8 hours at 82 C. The colour of the reaction batch changes to dark yellowish. After the end of the reaction, the reaction batch is precipitated by means of a dropping funnel with stirring in a vessel of water containing hydrochloric acid. (0174) The precipitated white reaction product is suspended with 2 liters of water and then filtered with suction by means of a G3 frit. The crude product obtained is dissolved again in 3.5 liters of a dilute sodium hydroxide solution (16 mol) and precipitated again in a vessel of water containing hydrochloric acid. The reprecipitated crude product is suspended several times with 2 liters of water and then filtered with suction each time. This wash procedure is repeated until the conductivity of the wash water is less than 15 muS. (0175) The product thus obtained is dried to constant mass at 90 C. in a vacuum drying cabinet. (0176) In each case the following yields are obtained after the experiment has been carried out 4 times: (0177) 1a) 950 g of a white solid (0178) 1b) 890 g of a white solid (0179) 1c) 1120 g of a white solid (0180) 1d) 1050 g of a white solid The melting point determination of the product gave 264 C. (0181) The characterization of the bisphenol obtained was effected by means of 1H-NMR spectroscopy |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; potassium iodide; In acetone; at 60℃; for 18h; | General procedure: Substituted phenol (20.00 mmol) was dissolved in acetone (40 mL) at room temperature, followed by addition of potassium carbonate (3.45 g, 25.00 mmol), potassium iodide (322mg, 2.00 mmol) and allyl bromide (3.03 g, 25.00 mmol). The reaction mixture was stirred for 18 h at 60 C. The solvent was removed in vacuo. The crude residue was diluted with NaOH 1N (30 mL) and extracted with ethyl acetate (3 x 40 mL). The combined organiclayers were washed with brine (1 x 30 mL), dried (Na2SO4), and the solvent was removed in vacuo. The crude mixture was used in the next step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | at 180℃; for 48h;Inert atmosphere; | Under nitrogen protection, 12.13 g (0.038 mol) of <strong>[77-09-8]phenolphthalein</strong> and 25 mL (0.19 mol) of N-(2-aminoethyl)morpholine were successively added to a 100 mL three-necked flask, magnetic stirring was started, and the temperature was gradually raised to 180 C. at the temperature. After stirring for 48 hours, the color of the solution turned reddish to yellowish, and the reaction solution was poured into a beaker containing a small amount of ethyl acetate. A white solid precipitated, which was filtered by suction and recrystallized from acetone to obtain the compound III (PPH-Mor).Mp: 270-272C, yield 89%.1H NMR (DMSO-d6): 9.47(2H,s), 7.69-7.71(1H,d), 7.52-7.57(1H,t), 7.40-7.47(2H,m), 6.97-7.00(4H,d), 6.74-6.77(4H) , d), 3.45 (4H, s), 2.09-2.12 (6H, d), 1.66-1.68 (2H, d). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | at 150℃; for 48h;Inert atmosphere; | Under nitrogen protection, 10.05 g (0.03 mol) of <strong>[77-09-8]phenolphthalein</strong> and 20 mL (0.15 mol) of N-(2-aminoethyl)pyrrolidine were successively added to a 100 mL three-necked flask, magnetic stirring was started, and the temperature was gradually raised to 150 C. at the temperature. After stirring for 48 hours, the color of the solution changed from red to reddish, and the reaction solution was poured into a beaker containing distilled water. A white solid precipitated, which was filtered by suction and recrystallized from ethyl acetate to give compound I (PPH-Py).Mp: 172-174C, yield 69%.1H NMR (DMSO-d6): 9.53 (2H, s), 7.63-7.65 (1H, d), 7.45-7.50 (1H, t), 7.33-7.41 (2H, m), 6.91-6.94 (4H, d), 6.68-6.71 (4H) ,d), 3.35-3.40(2H,t), 2.13(4H,s), 1.71-1.76(2H,t), 1.48(4H,s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | at 180℃; for 48h;Inert atmosphere; | Under nitrogen protection, 10.05 g (0.03 mol) of <strong>[77-09-8]phenolphthalein</strong> and 20 mL (0.15 mol) of N-(2-aminoethyl)piperidine were sequentially added to a 100 mL three-necked flask, magnetic stirring was started, and the temperature was gradually raised to 180 C. at the temperature. After stirring for 48 hours, the color of the solution turned reddish to yellowish, and the reaction solution was poured into a beaker containing distilled water. A white solid precipitated, which was filtered by suction and recrystallized from acetone to obtain compound II (PPH-Pi).Mp: 270-272 C., yield 78%. 1H NMR (DMSO-d6): 9.59 (2H, s), 7.68-7.70 (1H, d), 7.51-7.56 (1H, t), 7.39-7.47 ( 2H,m),6.96-6.99(4H,d),6.73-6.76(4H,d),3.42(2H,s),2.08(4H,s),1.59-1.64(2H,t),1.27-1.36 ( 6H,d). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35% | General procedure: 4,4'-([1,1'-biphenyl]-4,4'-diylbis(oxy))dibenzaldehyde (M1) was obtained according to the reference [36], following a slightly modified procedure. A mixture of 4,4?-dihydroxybiphenyl (100mg, 0.53mmol) and sodium hydroxide (52mg, 1.29mmol) was heated with stirring in 3ml DMSO at 100C, under strong nitrogen stream. After 6h, 4-fluorobenzaldehyde (149mg, 1.2mmol) was added dropwise to the reaction mixture and the temperature was raised to 120C. The reaction mixture was stirred for another 24h at this temperature, followed by cooling and pouring into water to precipitate the dialdehyde monomer. The purification was carried out by recrystallization from a mixture of tetrahydrofuran and ethanol, when 169mg of M1 was obtained as yellow powder with 80% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43.41% | With water; at 85℃; for 8h; | Compound 1 was prepared by according to the recently reported procedures with a slight modification [1]. In details, the mixture of <strong>[77-09-8]phenolphthalein</strong> (2.5466 g, 8 mmol), hexamethylenetetramine (1.6148 g, 11.5 mmol) and trifluoroacetic acid (40 mL) were added into a 250 flask and stirred at 85 C for 8 h. The unreacted trifluoroacetic acid is then removed by vacuum distillation, and solidarities with distilled water under stirring at 60 C for 30 min, solids are precipitated in an ice bath. The crude products were further purified by silica gel chromatography with 5:1 eluent of petroleum ether: ethyl acetate. Finally, a white solid product was obtained with a yield of 43.41%. IR (KBr, upsilon in cm-1): 3488, 3054, 2963, 1755, 1649, 1215, 1154, 802, 692. 1H NMR (400 MHz, DMSO-d6) :11.10 (s, 2H), 10.29 (s, 2H), 8.00 (d, 1H, J = 7.6 Hz), 7.93-7.88 (m, 2H), 7.75 (t, 1H, J = 7.24 Hz), 7.59 (d, 2H, J = 2.2 Hz), 7.51 (d, 1H, J =2.28 Hz), 7.50 (d, 1H, J = 2.28 Hz), 7.11 (s, 1H), 7.09 (s, 1H). 13C NMR (100 MHz, DMSO-d6): 191.02, 169,12, 161.48, 151.68, 135.79, 135.40, 131.79, 130.63, 126.66, 126.25, 124.80, 124.74, 122.26, 118.62, 90.59. |
1.3 g | With trifluoroacetic acid; at 70℃; for 8h; | 2.5466 g (8 ol) of phenol and 1.6148 g (11.5 mmol) of hexamethylenetetramine Dissolved in 40mL of trifluoroacetic acid, heated to 70 C with stirring and allowed to react for 8h, then rotary evaporation to remove excess trifluoroacetic acid; added 60mL Water was stirred under heating for 30mins; then cooled in an ice bath, and a white solid was precipitated as <strong>[77-09-8]phenolphthalein</strong> bisaldehyde. Yield: 1.30g. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
34% | Combine acetyl bromide-alpha-D-glucuronic acid methyl ester 5.0 g and<strong>[77-09-8]Phenolphthalein</strong> 4.0 g was added to a round-bottomed flask. After adding 25.0 mL of methanol, 1.46 g of silver oxide was added and reacted at room temperature for 8 h. After the reaction was completed, 2.0 g of NaOH was added while stirring. At room temperature, the reaction was performed for 4 h. After the reaction was completed, 17 mL of 10% was added Hydrochloric acid aqueous solution, adjust the pH to 2-3,After the polar solvent was removed by rotary evaporation, it was purified by a reverse phase column,That is, R1 and R2 are both compounds of the formula II structure of H, that is, <strong>[77-09-8]phenolphthalein</strong> beta-D-glucuronic acid, which is an off-white powder.Yield: 2.18 g; yield: 34%; HPLC content: 99.6%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With potassium carbonate In 1-methyl-pyrrolidin-2-one; water at 160 - 180℃; for 10h; Inert atmosphere; Autoclave; | 1-7 Example 7 Add 4.0L of NMP/water (4:1) mixed solvent to a stainless steel autoclave equipped with a water trap, and then phenolphthalein (2mol, 636g) and 3-aminopropanesulfonic acid (2.04mol, 284g) are suspended in In the solvent, a weak base potassium carbonate (1.02 mol, 141 g) was added under stirring conditions. Subsequently, vacuum degassed three times, heated to 160°C under nitrogen protection, and reacted for 4 hours. After the water output stabilized, the water separator valve was closed. The temperature was increased to 180°C, while the pressure was adjusted to 1.0 MPa, and the reaction was continued for 6 hours. After cooling to room temperature, dichloromethane was added and filtered. Washed with dichloromethane several times to obtain a solid powder. The conversion rate tested by proton nuclear magnetic resonance spectrum was 87.0%. Finally, the solid powder obtained by filtration is recrystallized with ethanol to obtain the target product, and the separation yield reaches more than 80%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | Stage #1: phenolphthalein With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 0.333333h; Inert atmosphere; Stage #2: 4-fluorobenzonitrile In N,N-dimethyl-formamide at 160℃; Inert atmosphere; | 2.2.1. Synthesis of monomer M2 (Procedure A) General procedure: Fluorescein 1b (166 mg, 0.5 mmol, 1 eq.), K2CO3 (691 mg, 5.0 mmol,10 eq), and DMF (3.0 mL) were charged in a Schlenk tube under Argon. The reaction mixture was allowed to stir at room temperature for 20 min before the addition of 4-fluorobenzonitrile 2 (242 mg, 2.0 mmol, 4 eq.) and the reaction mixture was refluxed overnight. The reaction mixture was then cooled to room temperature and the solvent was distilled under reduced pressure. The desired product was isolated by silica gel column chromatography using ethyl acetate/hexane (40:60 by volume) as eluent yielding a white solid (234 mg, yield = 85%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80.9% | Stage #1: phenolphthalein With pyridine In acetone at 0℃; for 0.5h; Green chemistry; Stage #2: p-toluenesulfonyl chloride In acetone for 12h; Green chemistry; | 2.4.1. Synthesis of phenolphthalein derivatives In the context of synthesizing heterocycles derived from phe-nolphthalein and studying their biological activity in subsequentstudies. This work was started with the reaction of phenolph-thalein with well-chosen electrophiles due to their efficiency inprevious applications [35 , 36 ]. Since sulfur compounds exhibit very significant biological activity [36-41] , the idea of synthesizing sul-fur compounds by the O-tosylation reaction of phenolphthalein( Scheme 1 ). To activate the O-alkylation reaction between the OHhydroxyl group and the active site of the electrophile, the pyridinewas initially used as a base to remove the two protons from thesymmetric OH groups. The use of other bases (Et 3 N, NaH, or DIEPA)3is possible.The phenolphthalein (0.2 g, 0.62 mmol) was dissolved in 8 ml°of acetone and then 10 ml of pyridine is added at 0C. The mix-ture is stirred magnetically until complete dissolution, after 30 minthe 4-toluenesulfonyl chloride (0.5 g, 2.62 mmol) is added to thereaction mixture in small portions. After 12 h of stirring, a TLCplate showed up the total transformation of the initial compoundand the appearance of a novel compound. The acetone was evap-orated in vacuo and the reaction mixture washed with water wasdecanted with dichloromethane. The solvent was evaporated; theresulting product is clarified by recrystallization from a mixture ofdichloromethane and methanol, filtered and dried in vacuo with ayield of 80.9%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96.8% | Stage #1: 3,3-bis(4'-hydroxyphenyl)-phthalide With triethylamine In propan-2-one at 0℃; for 0.5h; Green chemistry; Stage #2: benzoyl chloride In propan-2-one at 0℃; for 1h; Green chemistry; Stage #3: In propan-2-one at 20℃; for 16h; Green chemistry; | (3,3-bis(4-hydroxyphenyl)-2-benzofuran-1-one)bis(phenylmethanone) P2: Following the same strategy, the O alkylation reaction in thebasic medium of phenolphthalein R 1 and benzoyl chloride 2b performed according to the same mechanism is reported in this para-graph. This environmentally friendly synthetic method is econom-ical and leads to ((3-oxo-1, 3-dihydroisobenzofuran-1, 1-diyl) bis(4, 1-phenylene)) bis (phenylmethanone) with a very good yield( Scheme 2 ).To a solution of phenolphthalein (1 g, 3.14 mmol) dissolved in10 ml of acetone cooled to 0°C, 0.87 ml (6.28 mmol) of triethy-=lamine is added with stirring until pH14 so that the base cantear offthe two hydrogens of the OH group of phenolphthalein.The mixture is left stirring for 30 min, and then 0.87 ml (7,4 mmol)°of benzoyl chloride is added dropwise while stirring at 0C forone hour, then 16 h at room temperature. The acetone was evap-orated in vacuo and the reaction mixture washed with water wasdecanted with dichloromethane. The solvent was evaporated, andthe resulting product is clarified by recrystallization from a mix-ture of ether and methanol, filtered, and dried in vacuo. |
Tags: 77-09-8 synthesis path| 77-09-8 SDS| 77-09-8 COA| 77-09-8 purity| 77-09-8 application| 77-09-8 NMR| 77-09-8 COA| 77-09-8 structure
Precautionary Statements-General | |
Code | Phrase |
P101 | If medical advice is needed,have product container or label at hand. |
P102 | Keep out of reach of children. |
P103 | Read label before use |
Prevention | |
Code | Phrase |
P201 | Obtain special instructions before use. |
P202 | Do not handle until all safety precautions have been read and understood. |
P210 | Keep away from heat/sparks/open flames/hot surfaces. - No smoking. |
P211 | Do not spray on an open flame or other ignition source. |
P220 | Keep/Store away from clothing/combustible materials. |
P221 | Take any precaution to avoid mixing with combustibles |
P222 | Do not allow contact with air. |
P223 | Keep away from any possible contact with water, because of violent reaction and possible flash fire. |
P230 | Keep wetted |
P231 | Handle under inert gas. |
P232 | Protect from moisture. |
P233 | Keep container tightly closed. |
P234 | Keep only in original container. |
P235 | Keep cool |
P240 | Ground/bond container and receiving equipment. |
P241 | Use explosion-proof electrical/ventilating/lighting/equipment. |
P242 | Use only non-sparking tools. |
P243 | Take precautionary measures against static discharge. |
P244 | Keep reduction valves free from grease and oil. |
P250 | Do not subject to grinding/shock/friction. |
P251 | Pressurized container: Do not pierce or burn, even after use. |
P260 | Do not breathe dust/fume/gas/mist/vapours/spray. |
P261 | Avoid breathing dust/fume/gas/mist/vapours/spray. |
P262 | Do not get in eyes, on skin, or on clothing. |
P263 | Avoid contact during pregnancy/while nursing. |
P264 | Wash hands thoroughly after handling. |
P265 | Wash skin thouroughly after handling. |
P270 | Do not eat, drink or smoke when using this product. |
P271 | Use only outdoors or in a well-ventilated area. |
P272 | Contaminated work clothing should not be allowed out of the workplace. |
P273 | Avoid release to the environment. |
P280 | Wear protective gloves/protective clothing/eye protection/face protection. |
P281 | Use personal protective equipment as required. |
P282 | Wear cold insulating gloves/face shield/eye protection. |
P283 | Wear fire/flame resistant/retardant clothing. |
P284 | Wear respiratory protection. |
P285 | In case of inadequate ventilation wear respiratory protection. |
P231 + P232 | Handle under inert gas. Protect from moisture. |
P235 + P410 | Keep cool. Protect from sunlight. |
Response | |
Code | Phrase |
P301 | IF SWALLOWED: |
P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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